研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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Prospective evaluation of the relationship between response and exposure of total and unbound erlotinib in non-small cell lung cancer patients.

H. Kenmotsu, C.K. Imamura, T. Kawamura, T. Oyakawa, S. Omori, K. Nakashima, K. Wakuda, A. Ono, T. Taira, T. Naito, H. Murakami, N. Yamamoto, T. Takahashi, Y. Tanigawara

Cancer Chemother. Pharmacol 90 （ 2 ） 115 - 123 2022年07月

共著, 最終著者

Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials.

E. Booka, C.K. Imamura, M. Takeuchi, H. Kawakubo, H. Takeuchi, Y. Tanigawara, Y. Kitagawa, N. Boku

Gastric Cancer 25 （ 4 ） 770 - 782 2022年03月

研究論文（学術雑誌）, 共著

Pharmacometric analysis of seasonal influenza epidemics and the effect of vaccination using sentinel surveillance data.

Y. Otani, H. Kasai, Y. Tanigawara

CPT Pharmacometrics Syst Pharmacol 11 （ 1 ） 44 - 54 2022年

研究論文（学術雑誌）, 共著, 最終著者, 責任著者

Pharmacodynamic Model-based Safety Management of Eribulin-induced Myelosuppression in Patients with Breast Cancer.

H. Kasai, K.L. Poppenberg, V. Fermanelli, Y. Otani, Y. Tanigawara

Ther. Drug Monit. 2022年

研究論文（学術雑誌）, 共著, 最終著者, 責任著者

Pharmacometric analysis of seasonal influenza epidemics and the effect of vaccination using sentinel surveillance data

Otani, Y. Kasai, H. Tanigawara, Y.

CPT Pharmacometrics Syst Pharmacol 2021年10月

共著, 査読有り, ISSN 2163-8306

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Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application

M. Takeuchi, C. K. Imamura, E. Booka, H. Takeuchi, T. Mizukami, T. Kawakami, T. Funakoshi, K. Wakuda, Y. Aoki, Y. Hamamoto, M. Kitago, H. Kawakubo, N. Boku, Y. Tanigawara, Y. Kitagawa

Cancer Science 112 （ 2 ） 751 - 759 2021年02月

研究論文（学術雑誌）, 共著, 査読有り

Pharmacodynamic analysis of hypertension caused by lenvatinib using real-world postmarketing surveillance data

Y. Otani, H. Kasai, Y. Tanigawara

CPT Pharmacometrics Syst Pharmacol 2021年01月

研究論文（学術雑誌）, 共著, 査読有り

Population Pharmacokinetics of Voriconazole in Patients With Invasive Aspergillosis: Serum Albumin Level as a Novel Marker for Clearance and Dosage Optimization

P. Chantharit, M. Tantasawat, H. Kasai, Y. Tanigawara

Therapeutic Drug Monitoring 42 （ 6 ） 872 - 879 2020年12月

研究論文（学術雑誌）, 共著, 査読有り

Prediction of Fracture Risk From Early-Stage Bone Markers in Patients With Osteoporosis Treated With Once-Yearly Administered Zoledronic Acid

H. Kasai, Y. Mori, A. Ose, M. Shiraki, Y. Tanigawara

Journal of Clinical Pharmacology 2020年11月

研究論文（学術雑誌）, 共著, 査読有り

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Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer

T. Tsushima, H. Kasai, Y. Tanigawara

Cancer Chemotherapy and Pharmacology 86 （ 4 ） 487 - 495 2020年10月

研究論文（学術雑誌）, 共著, 査読有り

CYP2D6 Genotype-Guided Tamoxifen Dosing, in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase Ⅱ Study

K. Tamura, C.K. Imamura, T. Takano, S. Saji, T. Yamanaka, K, Yonemori, M. Takahashi, J. Tsurutani, R. Nishimura, K. Sato, A. Kitani, N. Ueno, T. Mushiroda, M. Kudo, Y. Fujiwara, Y. Tanigawara

Journal of Clinical Oncology 38 （ 6 ） 558 - 566 2020年02月

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Evaluation of gefitinib systemic exposure in EGFR-mutated non-small cell lung cancer patients with gefitinib-induced severe hepatotoxicity

T. Kawamura, C.K. Imamura, H. Kenmotsu, T. Taira, S. Omori, K. Nakashima, K. Wakuda, A. Ono, T. Naito, H. Murakami, T. Mushiroda, T. Takahashi, Y. Tanigawara

Cancer Chemotherapy and Pharmacology （Springer） 85 （ 3 ） 605 - 614 2020年02月

共著

Cerebrospinal pharmacokinetic and Pharmacodynamic Analysis of efficacy of meropenem in paediatric patients with bacterial meningitis

Y. Ohata, Y. Tomita, K. Sunakawa, G.L. Drusano, Y. Tanigawara

International Journal of Antimicrobial Agents （Elsevier） 54 292 - 300 2019年07月

研究論文（学術雑誌）, 共著

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer

Kawata, T. Higashimori, M. Itoh, Y. Tomkinson, H. Johnson, M. G. Tang, W. Nyberg, F. Jiang, H. Tanigawara, Y.

Cancer Chemotherapy and Pharmacology （Springer） 83 849 - 858 2019年02月

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Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration-Time Curve for Metastatic Renal-Cell Carcinoma

Y. Miura, C.K. Imamura, K. Uchino, T. Kishida, N. Matsubara, T. Shinojima, K. Kondo, F. Hongo, K. Yoshimura, Y. Tanigawara, T. Takano

Clinical Genitourinary Cancer 17 （ 1 ） e1 - e11 2019年02月

研究論文（学術雑誌）, 共著, 査読有り

Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen

T. Nakamura, K. Toshimoto, W. Lee, C. K. Imamura, Y. Tanigawara, Y. Sugiyama

CPT Pharmacometrics Syst Pharmacol 7 （ 7 ） 474 - 482 2018年07月

研究論文（学術雑誌）, 共著, 査読有り

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data

T. Kawamura, H. Kasai, V. Fermanelli, T. Takahashi, Y. Sakata, T. Matsuoka, M. Ishii, Y. Tanigawara

Cancer Science （Wiley） 109 2822 - 2829 2018年06月

共著, 査読有り

Modeling and simulation of bone mineral density in Japanese osteoporosis patients treated with zoledronic acid using tartrate-resistant acid phosphatase 5b, a bone resorption marker

Y. Mori, H. Kasai, A. Ose, M. Serada, M. Ishiguro, M. Shiraki, Y. Tanigawara

Osteoporosis International 29 （ 5 ） 1155 - 1163 2018年02月

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Clinical Factors Predicting Detection of T790M Mutation in Rebiopsy for EGFR-Mutant Non-small-cell Lung Cancer

T. Kawamura, H. Kenmotsu, S. Omori, K. Nakashima, K. Wakuda, A. Ono, T. Naito, H. Murakami, K. Omae, K. Mori, Y. Tanigawara, T. Nakajima, Y. Ohde, M. Endo, T. Takahashi,

Clin Lung Cancer 19 （ 2 ） 247 - 252 2017年08月

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Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

R. Kizu, K. Nishimura, R. Sato, K. Kosaki, T. Tanaka, Y. Tanigawara, T. Hasegawa

Horm. Res. Paediatr. 88 （ 5 ） 316 - 323 2017年07月

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Effect of everolimus on the glucose metabolic pathway in mouse skeletal muscle cells (C2C12)

Kayoko Yoshida, Chiyo K. Imamura, Kanako Hara, Mayumi Mochizuki, Yusuke Tanigawara

Metabolomics 13 （ 98 ） 2017年07月

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The effects of advanced age and serum alpha1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients

H. Kenmotsu, C.K. Imamura, A. Ono, S. Omori, K. Nakashima, K. Wakuda, T. Taira, T. Naito, H. Murakami, T. Takahashi, Y. Tanigawara

Br. J. Clin. Pharmacol 83 （ 11 ） 2416 - 2425 2017年07月

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Population Pharmacokinetic and Exposure-Response Analysis of Weekly Teriparatide in Osteoporosis Patients

A. Ose, M. Serada, K. Yamashita, K. Tsurui, Y. Tanigawara

J. Clin. Pharmacol 57 （ 12 ） 1545 - 1553 2017年06月

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Impact of cytochrome P450 2C19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with voriconazole

Imamura Chiyo K., Furihata Kenichi, Okamoto Shinichiro, Tanigawara Yusuke

Journal of Clinical Pharmacology 56 （ 4 ） 408 - 413 2016年04月

ISSN 0091-2700

This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg voriconazole twice daily at steady state. When tacrolimus was coadministered with voriconazole, a significant increase in area under its concentration-time curve (AUC_0-24) was observed for all genotypes. AUC_0-12 of voriconazole in IMs and PMs were significantly higher than that in EMs (P 0-24 of tacrolimus in combination with voriconazole in IMs and PMs were also significantly higher than that in EMs (P

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Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study

Booka Eisuke, Imamura Chiyo K., Takeuchi Hiroya, Hamamoto Yasuo, Gomi Daisuke, Mizukami Takuro, Ichiyama Takashi, Tateishi Kazunari, Takahashi Tsunehiro, Kawakubo Hirofumi, Soejima Kenzo, Boku Narikazu, Tanigawara Yusuke, Kitagawa Yuko

Gastric Cancer 19 （ 3 ） 876 - 886 2015年08月

ISSN 1436-3291

Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. Methods: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m2. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. Results: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9–108.8 mL/min as estimated by the Cockcroft–Gault equation. The S-1 dosage formula was derived as follows:(Formula presented.)where AUC is the area under the concentration–time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration–time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. Conclusions: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

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カルボプラチン投与量算出におけるCalvert式利用に関する実態調査

今村知世，加藤有紀子，下方智也，安藤雄一，谷川原祐介

医療薬学 41 （ 11 ） 759 - 767 2015年

Sunitinib-induced severe toxicities in a japanese patient with the ABCG2 421 AA genotype

Miura Yuji, Imamura Chiyo K., Fukunaga Koya, Katsuyama Yoshihiko, Suyama Koichi, Okaneya Toshikazu, Mushiroda Taisei, Ando Yuichi, Takano Toshimi, Tanigawara Yusuke

BMC Cancer 14 （ 964 ） 2014年12月

Background: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. Case presentation: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. Conclusion: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

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Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells

Suzuki Sayo, Tanigawara Yusuke

Proteome Science 12 （ 26 ） 2014年05月

Background: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. Our recent proteomics studies have demonstrated that intracellular protein expression levels of S100A10 are significantly correlated with the sensitivity of colorectal cancer (CRC) cells to L-OHP, but not 5-FU, suggesting that S100A10 is a candidate predictive marker for the response to L-OHP. In this study, we investigated whether S100A10 is involved in L-OHP sensitivity or not.Results: Forced expression of S100A10 in COLO-320 CRC cells significantly increased the 50% inhibitory concentration (IC₅₀) for L-OHP (P = 0.003), but did not change that for 5-FU, indicating that S100A10 is more specific to L-OHP than 5-FU. Silencing of the S100A10 gene showed no apparent effect on sensitivity to L-OHP in HT29 cells. Silencing of the annexin A2 (a binding partner of S100A10) gene alone downregulated both annexin A2 and S100A10 protein levels, with no change in S100A10 gene expression. However, original levels of intact S100A10 protein in CRC cells positively correlated with S100A10 mRNA levels (P = 0.002, R = 0.91).Conclusions: The present results have shown that protein expression of S100A10 was associated with resistance to L-OHP, but not 5-FU, supporting the hypothesis that S100A10 expression may predict L-OHP sensitivity. Thus, our present study provides basic findings to support that S100A10 expression can be used as a predictive marker for tumor sensitivity to L-OHP. © 2014 Suzuki and Tanigawara; licensee BioMed Central Ltd.

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Population PK modeling and simulation based on fluoxetine and norfluoxetine concentrations in milk : a milk concentration-based prediction model

124. R. Tanoshima, F. G. Bournissen, Y. Tanigawara, J. H. Kristensen, A. Taddio, K. F. Ilett, E. J. Begg, I. Wallach, S. Ito

British Journal of Clinical Pharmacology 78 （ 4 ） 918 - 928 2014年04月

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients

Hirasawa Akira, Zama Takeru, Akahane Tomoko, Nomura Hiroyuki, Kataoka Fumio, Saito Koichiro, Okubo Keisuke, Tominaga Eiichiro, Makita Kazuya, Susumu Nobuyuki, Kosaki Kenjiro, Tanigawara Yusuke, Aoki Daisuke

Journal of Human Genetics 58 （ 12 ） 794 - 798 2013年12月

ISSN 1434-5161

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients. © 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13.

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Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections

Tanigawara Yusuke, Kaku Mitsuo, Totsuka Kyoichi, Tsuge Hiroyuki, Saito Atsushi

Journal of Infection and Chemotherapy 19 （ 5 ） 858 - 866 2013年10月

ISSN 1341-321X

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC_0-24h/MIC and the fC _max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC_0-24h/MIC or fC _max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC_0-24h/MIC ≥ 30 and for fC _max/MIC ≥ 2 were 96.4 % and 96.3 %, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC_0-24h/MIC ≥ 30 and fC _max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations. © 2013 The Author(s).

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Pharmacogenetic determinants associated with sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell carcinoma patients

Kim Hye Ryun, Park Hyung Soon, Kwon Woo Sun, Lee Ji Hyun, Tanigawara Yusuke, Lim Sun Min, Kim Hyo Song, Shin Sang Jun, Ahn Jung Bae, Rha Sun Young

Cancer Chemotherapy and Pharmacology 72 （ 4 ） 825 - 835 2013年10月

ISSN 0344-5704

Purpose: The aim of this study was to investigate the pharmacogenetic determinants of sunitinib-related toxicity and ethnic difference in metastatic renal cell carcinoma (mRCC) among Korean patients. Methods: A pharmacogenetic study was performed in 65 patients with mRCC treated with the standard schedule of sunitinib (50 mg orally once daily for 4 weeks-on/2 weeks-off). Detailed data regarding the toxicity of sunitinib, including thrombocytopenia, neutropenia, anemia, and hand-foot syndrome (HFS), were prospectively collected in a clinical trial program (n = 38) or standard oncology practice (n = 27). Total of 12 genetic polymorphisms in 8 candidate genes (CYP1A1, CYP3A5, ABCB1, ABCG2, PDGFRα, VEGFR2, RET, and FLT3) were analyzed for an association with treatment-related toxicity from sunitinib using Pearson χ ² test. Results: Common grade 3 or grade 4 treatment-related toxicities were thrombocytopenia (36.9 %, 24/65), neutropenia (18.4 %, 12/65), anemia (7.7 %, 5/65), and HFS (12.3 %, 8/65). Patients carrying an ABCG2 421 AA genotype developed significantly more grade 3 or grade 4 thrombocytopenia, neutropenia, and HFS adjusted for age, sex, and Eastern Cooperative Oncology Group performance status, and body surface area (odds ratio compared with AC/CC genotypes [OR] 9.90, P = 0.04, thrombocytopenia; OR 18.20, P = 0.02, neutropenia; and OR 28.46, P = 0.01, HFS). In addition, total and surface protein ABCG2 protein expression was decreased in ABCG2 421 AA mutant cells compared to wild type. Conclusion: Among 12 genetic polymorphisms, polymorphism in the ABCG2 421C>A gene may be mostly associated with the risk of sunitinib-related toxicity in mRCC patients. Considering the high frequency of 421C>A SNP in Asian, this may be related to differential toxicities among ethnic groups. © 2013 Springer-Verlag Berlin Heidelberg.

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Clinical dose findings of sitafloxacin treatment : pharmacokinetic-pharmacodynamic analysis of two clinical trial results for community-acquired respiratory tract infections

Kohno Shigeru, Niki Yoshihito, Kadota Jun Ichi, Yanagihara Katsunori, Kaku Mitsuo, Watanabe Akira, Aoki Nobuki, Hori Seiji, Fujita Jiro, Tanigawara Yusuke

Journal of Infection and Chemotherapy 19 （ 3 ） 486 - 494 2013年06月

ISSN 1341-321X

The adequacy of sitafloxacin clinical dose regimens was assessed by comparing the efficacy of the administration of 100 mg sitafloxacin once daily (100 mg qd group) and 50 mg sitafloxacin twice daily (50 mg bid group). Patients with respiratory tract infections caused by pneumococci were orally treated with sitafloxacin (100 mg qd or 50 mg bid) for 7 days. The clinical efficacy, pneumococci eradication rate, safety, and pharmacokinetic and pharmacodynamic indices of the two groups were then assessed. The clinical efficacy was 93.5 % in both groups. The pneumococci eradication rate was 98.2 % in the 100 mg qd group and 92.7 % in the 50 mg bid group. The mean of the free AUC _0-24h divided by the minimum inhibitory concentration (MIC) (fAUC_0-24h/MIC) did not differ significantly between the 100 mg qd (103.24) and the 50 mg bid groups (105.25). The mean of the free C _peak divided by the MIC (fC _peak/MIC) was higher in the 100 mg qd group (10.19) than in the 50 mg bid group (6.53). The pathogen eradication rate was 98.9 % (89/90) when the fAUC_0-24h/MIC was greater than 30, and the eradication rate was 98.9 % (89/90) when the fC _peak/MIC was greater than 2. The incidences of adverse drug reactions were 33.7 % in the 100 mg qd group and 40.4 % in the 50 mg bid group. No obvious differences in the efficacy and safety were observed between the dosage groups. For cases in which a sufficiently high C _peak is necessary to ensure the susceptibility of the pathogens to the drug, 100 mg sitafloxacin once daily should be administered. © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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Clinical and bacteriological efficacies of sitafloxacin against community-acquired pneumonia caused by Streptococcus pneumonia : nested cohort within a multicenter clinical trial

Fujita Jiro, Niki Yoshihito, Kadota Jun Ichi, Yanagihara Katsunori, Kaku Mitsuo, Watanabe Akira, Aoki Nobuki, Hori Seiji, Tanigawara Yusuke, Cash Haley L., Kohno Shigeru

Journal of Infection and Chemotherapy 19 （ 3 ） 472 - 479 2013年06月

ISSN 1341-321X

We evaluated the clinical and bacteriological efficacy of oral sitafloxacin (STFX) in clinically diagnosed community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae. Additionally, we cultured these patient samples to test the minimal inhibitory concentrations (MICs) of levofloxacin (LVFX), moxifloxacin (MFLX), STFX, and penicillin G (PCG), as well as identified mutations in the quinolone resistance determinant regions (QRDRs) in LVFX-resistant strains. This study is a nested cohort from a prospective, multicenter clinical trial consisting of 139 patients with community-acquired pneumonia (CAP), from which 72 were included in this study. After diagnosis of CAP caused by S. pneumoniae, STFX (50 mg twice daily, or 100 mg once daily) was orally administered for 7 days. Sixty-five patient sputum samples were then cultured for MIC analysis. In a LVFX-resistant strain that was identified, mutations in the QRDRs of the gyrA, gyrB, parC, and parE genes were examined. Of 72 patients eligible for this study, S. pneumoniae was successfully cultured from the sputum of 65 patients, and only 7 patients were diagnosed by urinary antigen only. Clinical improvement of CAP was obtained in 65 of the 69 clinically evaluable patients (65/69, 94.2 %). Eradication of S. pneumoniae was observed in 62 patients of the 65 bacteriologically evaluable patients (62/65, 95.4 %). Additionally, STFX showed the lowest MIC distribution compared with LVFX, MFLX, and PCG, and no major adverse reactions were observed. STFX treatment in patients with CAP caused by S. pneumoniae was found to be highly effective both clinically (94.2 %) and bacteriologically (95.4 %). © 2012 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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Blood-direct InvaderPlus® as a new method for genetic testing

Hirasawa Akira, Akahane Tomoko, Tanigawara Yusuke, Aoki Daisuke

Personalized Medicine 9 （ 6 ） 657 - 663 2012年08月

ISSN 1741-0541

Aim: This study compared the efficiency of Blood-direct InvaderPlus® with existing methods for detecting genetic polymorphisms by using clinical samples, and to determine whether this new method can be used for future clinical studies. Materials & methods: We developed a new method, called Blood-direct InvaderPlus, for detecting genetic polymorphisms. Whole-blood samples were subjected to genetic analysis with the new method and also the conventional method. Results: The results obtained with the new method were consistent with those of direct sequencing. Blood-direct InvaderPlus was able to detect gene polymorphisms of UGT1A16,27,28,60, VKORC1 -1639G>A, VKORC1 1173T>C and CYP2C92 and3 much faster than the conventional methods. Conclusion: Blood-direct InvaderPlus allowed accurate, simple and rapid detection of genetic polymorphisms. © 2012 Future Medicine Ltd.

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Pharmacokinetics of mizoribine in adult living donor liver transplantation

Shinoda M., Tanabe M., Kawachi S., Ono Y., Hayakawa T., Iketani O., Kojima M., Itano O., Obara H., Kitago M., Hibi T., Matsubara K., Shimojima N., Fuchimoto Y., Hoshino K., Wakabayashi G., Shimazu M., Tanigawara Y., Kuroda T., Morikawa Y., Kitajima M., Kitagawa Y.

Transplantation Proceedings 44 （ 5 ） 1329 - 1335 2012年06月

ISSN 0041-1345

We investigated the pharmacokinetics of mizoribine in the acute phase after adult living donor liver transplantation (LDLT). Between February 2004 and October 2009, 16 recipients received immunosuppressive therapy that included mizoribine (100 to 200 mg/d) after undergoing LDLT. We determined the serum levels of mizoribine before (C0) and 3 (C3), 4 (C4), and 10 (C10) hours after administration on postoperative days 3, 7, and 21. We assessed area under the concentration time curve (AUC) (hour · μg/mL), normalized serum concentration (NSC) at C0 [concentration (μg/mL)/dose (mg/kg body weight)], and estimated glomerular filtration rate (eGFR). The mizoribine concentration showed increases at C3 and C4 followed by a decrease at C10 on all days. AUC was 4.3, 5.9, and 8.3 in the 200-mg/d dose group on days 3, 7, and 21, respectively. NSC at C0 increased for 3 weeks after LDLT. There was a significant correlation between the NSC at C0 and eGFR on day 21, but not on days 3 and 7. There were no correlations between the NSC at C0 and either aspartate aminotransferase, total bilirubin, albumin, trough cyclosporine, or trough tacrolimus on any day. The pharmacokinetics of mizoribine in the acute phase after LDLT seems to be affected by postoperative day and renal function. © 2012 Elsevier Inc.

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Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

Matsuoka Hiromichi, Arao Tokuzo, Makimura Chihiro, Takeda Masayuki, Kiyota Hidemi, Tsurutani Junji, Fujita Yoshihiko, Matsumoto Kazuko, Kimura Hideharu, Otsuka Masatomo, Koyama Atsuko, Imamura Chiyo K., Tanigawara Yusuke, Yamanaka Takeharu, Tanaka Kyoko, Nishio Kazuto, Nakagawa Kazuhiko

Oncology Reports 27 （ 5 ） 1393 - 1399 2012年05月

ISSN 1021-335X

Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naïve cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRM1, 118A→G) and catechol-O-methyltransferase (COMT, 472G→A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the mRNA expression levels of arrestin β 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRM1 and morphine treatment; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G→A genotype may be a predictive biomarker of the response to morphine treatment.

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A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese

Kiyotani Kazuma, Mushiroda Taisei, Tsunoda Tatsuhiko, Morizono Takashi, Hosono Naoya, Kubo Michiaki, Tanigawara Yusuke, Imamura Chiyo K., Flockhart David A., Aki Fuminori, Hirata Koichi, Takatsuka Yuichi, Okazaki Minoru, Ohsumi Shozo, Yamakawa Takashi, Sasa Mitsunori, Nakamura Yusuke, Zembutsu Hitoshi

Human Molecular Genetics 21 （ 7 ） 1665 - 1672 2012年04月

ISSN 0964-6906

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 singlenucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P 5 2.87 3 10^-9.9.4× 10^-8). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrencefree survival in the replication study (log-rank P 5 2.02 × 10^-4) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (logrank P 5 1.26 × 10-10). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P 5 6.29 × 10^-9]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P 5 2.28 × 10^-12). © The Author 2011. Published by Oxford University Press. All rights reserved.

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Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation

Tanigawara Yusuke, Nozawa Kenji, Tsuda Hisatsugu

European Journal of Clinical Pharmacology 68 （ 1 ） 39 - 53 2012年01月

ISSN 0031-6970

Purpose: Garenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens. Methods: At the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration-time curve divided by the minimum inhibitory concentration (fAUC _0-24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases. Results: Logistic regression analysis showed that fAUC _0-24/MIC ratio was a significant variable that predicted clinical response (p∈=∈0.0164). Of all subjects, 92.4% reached the target value of fAUC _0-24/MIC ratio∈>∈30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC _0-24 and maximum concentration) and the incidence of adverse events by the Mann-Whitney test. Conclusions: The antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations. © 2011 The Author(s).

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Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients

Kiyotani Kazuma, Mushiroda Taisei, Imamura Chiyo K., Tanigawara Yusuke, Hosono Naoya, Kubo Michiaki, Sasa Mitsunori, Nakamura Yusuke, Zembutsu Hitoshi

Breast Cancer Research and Treatment 131 （ 1 ） 137 - 145 2012年01月

ISSN 0167-6806

CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography-tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level. © 2011 Springer Science+Business Media, LLC.

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S100A10 protein expression is associated with oxaliplatin sensitivity in human colorectal cancer cells

Suzuki Sayo, Yamayoshi Yasuko, Nishimuta Akito, Tanigawara Yusuke

Proteome Science 9 2011年12月

Background: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. The objective of our study was to find candidate protein markers for tumor sensitivity to L-OHP from intracellular proteins of human colorectal cancer (CRC) cell lines. We performed expression difference mapping (EDM) analysis of whole cell lysates from 11 human CRC cell lines with different sensitivities to L-OHP by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), and identified a candidate protein by liquid chromatography/mass spectrometry ion trap time-of-flight (LCMS-IT-TOF).Results: Of the qualified mass peaks obtained by EDM analysis, 41 proteins were differentially expressed in 11 human colorectal cancer cell lines. Among these proteins, the peak intensity of 11.1 kDa protein was strongly correlated with the L-OHP sensitivity (50% inhibitory concentrations) (P < 0.001, R ²= 0.80). We identified this protein as Protein S100-A10 (S100A10) by MS/MS ion search using LCMS-IT-TOF. We verified its differential expression and the correlation between S100A10 protein expression levels in drug-untreated CRC cells and their L-OHP sensitivities by Western blot analyses. In addition, S100A10 protein expression levels were not correlated with sensitivity to 5-fluorouracil, suggesting that S100A10 is more specific to L-OHP than to 5-fluorouracil in CRC cells. S100A10 was detected in cell culture supernatant, suggesting secretion out of cells.Conclusions: By proteomic approaches including SELDI technology, we have demonstrated that intracellular S100A10 protein expression levels in drug-untreated CRC cells differ according to cell lines and are significantly correlated with sensitivity of CRC cells to L-OHP exposure. Our findings provide a new clue to searching predictive markers of the response to L-OHP, suggesting that S100A10 is expected to be one of the candidate protein markers. © 2011 Suzuki et al; licensee BioMed Central Ltd.

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Optimal treatment schedule of meropenem for adult patients with febrile neutropenia based on pharmacokinetic-pharmacodynamic analysis

Ohata Yuka, Tomita Yoshiko, Nakayama Mitsunobu, Tamura Kazuo, Tanigawara Yusuke

Journal of Infection and Chemotherapy 17 （ 6 ） 831 - 841 2011年12月

ISSN 1341-321X

The objectives of this study were to develop a population pharmacokinetic (PK) model of meropenem, to simulate the percent time above minimum inhibitory concentration (%T > MIC) at various MICs, and to estimate effective dosage regimens by calculating the target attainment rates against various strains of bacteria. A total of 209 plasma samples (1-3 concentrations per patient) were obtained from 98 adult Japanese patients with febrile neutropenia in an open-labeled Phase 3 study. The final population PK model was fit to a two-compartment model with zero-order input. Creatinine clearance had a positive significant correlation with CL. Gender had a significant effect on Vc; however, this effect was small, and the PK profile in male patients was similar to that in female patients. The population PK parameters developed in this study are useful in simulating PK profiles of meropenem at various dosage regimens precisely for calculation of %T > MIC. The PK-PD analysis indicated that 0.5 g every 6 h (q6h) was more effective than 1 g q12h, although provided 2 g per day in total. A meropenem dosage regimen of 1 g q8h and/or longer infusion duration was better against a pathogen of comparatively low sensitivity, Pseudomonas aeruginosa (for MIC ≥2 μg/ml). Although causative bacteria were identified in a small number of patients, the target attainment rates at 75%T > MIC (89%) were comparable to microbiological response (89%). The present PK-PD analyses under various conditions are useful in the treatment of febrile neutropenia. © 2011 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

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A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures - A randomized, active comparator, double-blind study

Matsumoto Toshio, Ito Masako, Hayashi Yasufumi, Hirota Takako, Tanigawara Yusuke, Sone Teruki, Fukunaga Masao, Shiraki Masataka, Nakamura Toshitaka

Bone 49 （ 4 ） 605 - 612 2011年10月

ISSN 8756-3282

Background: Eldecalcitol is an analog of 1,25-dihydroxyvitamin D ₃ that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456. Methods and results: This 3year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75μg eldecalcitol versus 1.0μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92years old were randomly assigned 1:1 to receive eldecalcitol (n=528) or alfacalcidol (n=526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (<50nmol/L) were Supplemented with 400IU/day vitamin D ₃. Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56-0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11-0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups. Conclusions: Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol. © 2011 Elsevier Inc.

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Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects

Tsuruta Kazuhisa, Yamada Yoshinobu, Serada Masashi, Tanigawara Yusuke

Journal of Clinical Pharmacology 51 （ 9 ） 1276 - 1285 2011年09月

ISSN 0091-2700

Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concentration data obtained in phase 1 (20 patients, 348 time points) and phase 2 (116 patients, 305 time points) clinical trials. The actual and predicted plasma concentrations of thrombomodulin alfa based on the final PPK model showed a good linear correlation (R = 0.9504), and the pharmacokinetics of thrombomodulin alfa in DIC patients were affected by body weight, age, renal dysfunction, and hematocrit value. The distribution volume and clearance (CL) were proportional to body weight and were significantly increased in patients with lower hematocrit value (male <40%, female <35%). Furthermore, CL was decreased in patients with renal dysfunction and in elderly patients. Based on these results, the standard dose of thrombomodulin alfa is adjusted according to body weight. However, further dose adjustment is not needed based on age and hematocrit value, since these factors did not cause the large changes in plasma concentration that can affect the efficacy or safety. © 2011 The Author(s).

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Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Watanabe Mitsuhiro, Horai Yasushi, Houten Sander M., Morimoto Kohkichi, Sugizaki Taichi, Arita Eri, Mataki Chikage, Sato Hiroyuki, Tanigawara Yusuke, Schoonjans Kristina, Itoh Hiroshi, Auwerx Johan

Journal of Biological Chemistry 286 （ 30 ） 26913 - 26920 2011年07月

ISSN 0021-9258

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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Overview of the clinical pharmacokinetics of eldecalcitol, a new active vitamin D₃ derivative

Abe Masaichi, Tsuji Naoki, Takahashi Fumiaki, Tanigawara Yusuke

Japanese Pharmacology and Therapeutics 39 （ 3 ） 261 - 274 2011年03月

ISSN 0386-3603

Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. as a treatment with the potential of becoming the drug of first choice for osteoporosis, is a new derivative of active vitamin D₃ (1,25(OH) ₂D₃) with a hydroxypropyloxy group introduced at the 2β position. The clinical development of this product has included a Phase I multiple dose study, early and late Phase II studies, a Phase III study, a clinical pharmacology study to investigate pharmacokinetics in postmenopausal women, a drug interaction study, a bioequivalence formulation study and a clinical pharmacology study to investigate pharmacokinetics in patients with impaired liver function. Using data from all these studies, we sought to characterize the pharmacokinetic profile of eldecalcitol.

Pharmacokinetics of eldecalcitol in primary osteoporosis patients - Randomized, double-blind, multicentre, long-term phase III clinical study

Miyata Kumiko, Abe Masaichi, Terao Kimio, Kawanishi Takehiko, Tsuji Naoki, Shiraki Masataka, Nakamura Toshitaka, Matsumoto Toshio, Tanigawara Yusuke

Japanese Pharmacology and Therapeutics 39 （ 3 ） 299 - 307 2011年03月

ISSN 0386-3603

Background: Eldecalcitol, which was developed by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan) as a treatment for osteoporosis, is a new derivative of active vitamin D₃(1,25 (OH)₂D₃) with a hydroxypropyloxy group introduced at the 2β position. A Phase III, alfacalcidol-controlled clinical study of eldecalcitol was conducted in primary osteoporosis patients, with the incidence of new, non-traumatic vertebral fractures designated as the primary endpoint. Objectives: The objective of this study was to characterize the pharmacokinetic profile of eldecalcitol, using data obtained from this Phase III clinical study in primary osteoporosis patients. Methods: Patients were randomly assigned to an oral eldecalcitol or alfacalcidol group. Patients in the eldecalcitol group took one capsule each of eldecalcitol 0.75 μg and alfacalcidol placebo, while those in the alfacalcidol group took one capsule each of eldecalcitol placebo and alfacalcidol 1.0 μg, once daily for 144 weeks. Efficacy and safety in patients on eldecalcitol were compared with those in patients on alfacalcidol. For the pharmacokinetic analysis, the serum eldecalcitol concentration was measured at 48, 72, 96 and 144 weeks. Results: In the eldecalcitol group, the mean trough serum eldecalcitol concentrations obtained from patients without dose reduction at the time of blood collection were 286.9, 320.1, 387.3 and 344.0 pg/mL at 48, 72, 96 and 144 weeks, respectively. At all times, the trough serum eldecalcitol concentration remained within the range of values at 72 weeks. It was concluded from these results that the serum eldecalcitol concentration had reached steady state by 48 weeks. Calculation of the trough serum eldecalcitol concentration by baseline characteristic showed that the concentration was in a similar range in all categories of age, renal function and vitamin D supplementation. Conclusions: The trough serum eldecalcitol concentration in patients receiving eldecalcitol 0.75 μg did not change substantially from 48 to 144 weeks after starting treatment, suggesting that the pharmacokinetics of eldecalcitol do not vary with long-term treatment. Analysis using trough serum eldecalcitol concentrations revealed that age, renal function and vitamin D supplementation had no substantial effect on pharmacokinetics.

Levofloxacin 注射剤の母集団薬物動態／薬力学解析

谷川原祐介，清水貴子，戸塚恭一

日本化学療法学会雑誌 59 （ S-1 ） 55-63 2011年

研究論文（学術雑誌）, 共著, 査読有り

Optimal dosage regimen of meropenem for pediatric patients based on pharmacokinetic/pharmacodynamic considerations

Ohata Yuka, Tomita Yoshiko, Nakayama Mitsunobu, Kozuki Tsuneo, Sunakawa Keisuke, Tanigawara Yusuke

Drug Metabolism and Pharmacokinetics 26 （ 5 ） 523 - 531 2011年

ISSN 1347-4367

A population pharmacokinetic (PK) model for meropenem in Japanese pediatric patients with various infectious diseases was developed based on 116 plasma concentrations from 50 pediatric patients. The population PK parameters developed in this analysis are useful for calculation of the percent time above minimum inhibitory concentration (%T>MIC) and for optimal dosing of meropenem in pediatric patients. After dosing at 20mg/kg t.i.d. by 0.5-h infusion (approved standard dose for pediatric patients in Japan), the target value of 50%T>MIC was achieved, indicating that 20mg/kg t.i.d. by 0.5-h infusion is effective for susceptible bacteria. In contrast, for bacteria with higher MICs such as Pseudomonas aeruginosa (MIC ≥ 2 μg/mL), the probability of target attainment of 50%T>MIC was 60.7% at a dose of 40mg/kg t.i.d. by 0.5-h infusion (highest dose approved for pediatric patients in Japan). The simulations described in this article indicated that 40 mg/kg t.i.d. with a longer infusion duration (e.g., 4 h) is more effective against bacteria with a MIC higher than 2 μg/mL. The predicted probability of target attainment for 50%T>MIC (97.0%) was well correlated not only to the microbiological efficacy rate (97.0%) but also to the clinical efficacy rate (95.9%) in the present phase 3 study. © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Kiyotani Kazuma, Mushiroda Taisei, Imamura Chiyo K., Hosono Naoya, Tsunoda Tatsuhiko, Kubo Michiaki, Tanigawara Yusuke, Flockhart David A., Desta Zeruesenay, Skaar Todd C., Aki Fuminori, Hirata Koichi, Takatsuka Yuichi, Okazaki Minoru, Ohsumi Shozo, Yamakawa Takashi, Sasa Mitsunori, Nakamura Yusuke, Zembutsu Hitoshi

Journal of Clinical Oncology 28 （ 8 ） 1287 - 1293 2010年03月

ISSN 0732-183X

Purpose: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods: We studied 282 patients with hormone receptor-positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion: Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen. © 2010 by American Society of Clinical Oncology.

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Pharmacokinetics of S-1 and CYP2A6 genotype in Japanese patients with advanced cancer

Hirose Takashi, Fujita Ken Ichi, Nishimura Kazuko, Ishida Hiroo, Yamashita Keishi, Sunakawa Yu, Mizuno Keiko, Miwa Keisuke, Nagashima Fumio, Tanigawara Yusuke, Adachi Mitsuru, Sasaki Yasutsuna

Oncology Reports 24 （ 2 ） 529 - 536 2010年

ISSN 1021-335X

We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentrationtime curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m²/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wildtype, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wildtype or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.

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抗MRSA薬のTDMに関する全国アンケート調査

小林昌宏，竹末芳生，谷川原祐介，三鴨廣繁，木村利美，平田純生，白石　正，栄田敏之，高倉俊二

日本化学療法学会雑誌 58 （ 2 ） 119-124 2010年

研究論文（学術雑誌）, 共著, 査読有り

母集団薬物動態解析による硫酸アルベカシンの成人患者における1日1回投与法の有用性検討

佐藤信雄，三浦有紀，三富奈由，林　宏行，鈴木　尚，芝崎茂樹，黒沢　亨，谷川原祐介

ＴＤＭ研究 27 （ 2 ） 98-110 2010年

研究論文（学術雑誌）, 単著, 査読有り

硫酸アルベカシンの血中濃度モニタリング施行患者に対する特定使用成績調査

河野　仁，谷川原祐介

ＴＤＭ研究 27 （ 2 ） 55-71 2010年

研究論文（学術雑誌）, 単著, 査読有り

小児及び成人の通年性アレルギー性鼻炎患者に対するロラタジン投与試験　有効性及び安全性に関する報告

鈴木五男, 谷川原祐介

アレルギー・免疫 16 （ 12 ） 1966 - 1978 2009年11月

共著

Carboplatinの血中濃度モニタリングに基づいた血液透析スケジュール設定が有用であった慢性腎不全合併肺癌患者の１例

鎌田　浩史，浅野　浩一郎，副島　研造，白畑　亨，中谷　理恵，稲本　元，池谷　修，山吉　康子，谷川原　祐介，石坂　彰敏，

Japanese Journal of Cancer and Chemotherapy 36 （ 9 ） 1529 - 1532 2009年09月

ISSN 0385-0684

A 69-year-old woman undergoing hemodialysis due to ANCA-associated nephritis and chronic renal failure developed lung adenocarcinoma and underwent radical surgery. Upon recurrence of her cancer, she received combination chemotherapy with carboplatin (CBDCA) 150 mg/m² and docetaxel 35-70 mg/m². Concentration of free CBDCA in serum was monitored for 6 days after drug administration. Hemodialysis was performed 1 hour after administration of CBDCA, and on day 4. Despite the lower maximum concentration, serum CBDCA levels 20-24 h after chemotherapy in this patient were 15 to 20 times higher than in subjects with normal renal function who received CBDCA at the area under the curve (AUC) of 5. She experienced moderate to severe nausea and vomiting which persisted for 12 days. During her second course of chemotherapy, hemodialysis was performed for 3 consecutive days after drug administration. The serum CBDCA levels on day 2 or later remained lower than in the first course, and the patient experienced fewer severe side effects. Based on the data from therapeutic drug monitoring of CBDCA, hemodialysis for 3 consecutive days after drug administration has been demonstrated to be useful for treatment of a patient with chronic renal failure receiving chemotherapy with CBDCA.

Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmatics

Asano Koichiro, Nakade Susumu, Shiomi Tetsuya, Nakajima Takeshi, Suzuki Yusuke, Fukunaga Koichi, Oguma Tsuyoshi, Sayama Koichi, Fujita Hirofumi, Tanigawara Yusuke, Ishizaka Akitoshi

Respirology 14 （ 6 ） 822 - 827 2009年08月

ISSN 1323-7799

Background and objective: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC₄ synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC₄ synthase gene polymorphisms, were also investigated. Methods: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV₁ after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Results: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC ₄ synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). Conclusions: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug. © 2009 The Authors.

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A phase I escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors.

K. Shirao, T. Yoshino, N. Boku, K. Kato, T. Hamaguchi, H. Yasui, N. Yamamoto, Y. Tanigawara, A. Nolting, S. Yoshino

Cancer Chemotherap. Pharmacol 64 （ 3 ） 557-564 2009年

研究論文（学術雑誌）, 共著, 査読有り

Levofloxacin 500mg 経口投与時の母集団薬物動態／薬力学解析

谷川原祐介,清水貴子,戸塚恭一

日本化学療法学会雑誌 57 （ S-2 ） 47-54 2009年

研究論文（学術雑誌）, 共著, 査読有り

A pharmacokinetic and dose escalation study of pegfilgrastim (KRN125) in lung cancer patients with chemotherapy-induced neutropenia

Yamamoto Nobuyuki, Sekine Ikuo, Nakagawa Kazuhiko, Takada Minoru, Fukuoka Masahiro, Tanigawara Yusuke, Saijo Nagahiro

Japanese Journal of Clinical Oncology 39 （ 7 ） 425 - 430 2009年

ISSN 0368-2811

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts <0.5 × 10⁹ cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 μg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration - time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia. © The Author (2009). Published by Oxford University Press. All rights reserved.

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Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport

Takara Kohji, Sakaeda Toshiyuki, Kakumoto Mikio, Tanigawara Yusuke, Kobayashi Hironao, Okumura Katsuhiko, Ohnishi Noriaki, Yokoyama Teruyoshi

Oncology Research 17 （ 11-12 ） 527 - 533 2009年

ISSN 0965-0407

The purpose of this study is to examine the effects of doxazosin, an α-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvr100-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [³H]vinblastine, [3H]daunorubicin, and [³H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK₁ cells. The sensitivity to vinblastine and paclitaxel of Hvr100-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 μM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 μM had a reversal effect on the sensitivity to vinblastine, whereas terazosin had no effect. In transport experiments, doxazosin concentration dependently increased the apical-to-basal transport of radiolabeled drugs in LLC-GA5-COL150 cells, but did not show remarkable effects on the basal-to-apical transport. In addition, doxazosin restored the intracellular accumulation in a concentration-dependent manner in LLC-GA5-COL150 cells. Doxazosin may partly reverse MDR by inhibiting MDR1-mediated transport, making it a candidate lead compound in the development of a reversing agent for MDR. Copyright © 2009 Cognizant Comm. Corp.

Comparative pharmacodynamics of olmesartan and azelnidipine in patients with hypertension: a population pharmacokinetic/pharmacodynamic analysis

Tanigawara Yusuke, Yoshihara Kazutaka, Kuramoto Kizuku, Arakawa Kikuo

Drug Metabolism and Pharmacokinetics 24 （ 4 ） 376 - 388 2009年

ISSN 1347-4367

The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E_max) of olmesartan, whereas azelnidpine E_max was independent of patient background characteristics investigated. No patient was found to have a high E_max to one agent who also had a high E_max to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

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血中濃度モニタリングに基づくアミカシン，トブラマイシンの用量最適化と治療効果の向上

武田香陽子，池谷　修，山吉康子，早川智久，青柳修一，森田邦彦，谷川原祐介

ＴＤＭ研究（TDM研究） 25 （ 4 ） 180 - 186 2008年10月

院内製剤「人工髄液CSF-19」の開発と調製実績

山口雅也，市村健一，矢島　茂，佐々木　隆，谷川原祐介

薬剤学 68 （ 5 ） 371-377 2008年10月

研究論文（学術雑誌）, 共著, 査読有り

Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma

Hattori Yutaka, Okamoto Shin Ichiro, Shimada Naoki, Kakimoto Tsunayuki, Morita Kunihiko, Tanigawara Yusuke, Ikeda Yasuo

Cancer Science 99 （ 6 ） 1243 - 1250 2008年06月

ISSN 1347-9032

We previously reported a pilot study of thalidomide monotherapy for Japanese patients with refractory or relapsed multiple myeloma. In the present work, we have extended this clinical trial to a single-institute phase 2 study with a larger number of patients and longer follow-up time. New information on the optimal dose and prognostic factors as well as the correlation of toxicities with treatment schedule was obtained. Fifteen of 56 (27%) patients achieved a partial response, including three cases with near-complete remission. Most patients suffered toxicities at a dose of 400 mg per day, but there was no clear dose-response relationship. Thus, a lower dose such as 200.mg per day or less is considered optimal. Multivariate analyses identified only lack of response to therapy as an adverse prognostic factor for progression-free survival. Chromosomal abnormality, C-reactive protein. >10 mg/L, and more than six previous courses of chemotherapy were significantly associated with shorter overall survival. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 23 and 11% of patients, respectively. Grade 4 interstitial pneumonia and grade 5 pulmonary hypertension were observed; however, no patient suffered deep vein thrombosis, which has frequently been observed in other studies. Duration of therapy was closely related to the development of peripheral neuropathy. The efficacy and prognostic factors of this treatment were confirmed in long-term observation. However, special attention should be paid to toxicities such as hematological and pulmonary complications as well as peripheral neuropathy in long-term users. © 2008 Japanese Cancer Association.

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Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada Y., Tahara M., Miya T., Satoh T., Shirao K., Shimada Y., Ohtsu A., Sasaki Y., Tanigawara Y.

British Journal of Cancer 98 （ 6 ） 1034 - 1038 2008年03月

ISSN 0007-0920

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35-40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m^-2 (level 1) or 130 mg m^-2 (level 2) on day 1, and S-1 (80-120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2-14), RR of 50% (1 CR and 13 PR: 95% CI 31-69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access. © 2008 Cancer Research UK.

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Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole

Mihara Ai, Mori Takehiko, Aisa Yoshinobu, Yamazaki Rie, Iketani Osamu, Tanigawara Yusuke, Ikeda Yasuo, Okamoto Shinichiro

European Journal of Clinical Pharmacology 64 （ 1 ） 89 - 91 2008年01月

ISSN 0031-6970

Objective: Although the drug interaction between fluconazole and calcineurin inhibitors has been established, the influence of the route of fluconazole administration on its drug interaction with calcineurin inhibitors has yet to be fully examined. The aim of the present study is to examine whether different routes of fluconazole administration alter its drug interactions with intravenous calcineurin inhibitors. Methods: In 53 recipients of allogeneic hematopoietic cell transplantation receiving calcineurin inhibitors intravenously, steady-state whole-blood levels of cyclosporine A (CsA) or tacrolimus were measured after the route of fluconazole (200 mg/day) administration was switched from intravenous to oral. Results: The mean steady-state whole-blood level of CsA or tacrolimus significantly increased after the route of fluconazole administration was switched from intravenous to oral (CsA: to 394±28.4 from 362±17.8 ng/mL; tacrolimus: to 18.8±0.64 from 17.4±0.39 ng/mL, P<0.05). Conclusion: This finding strongly suggests that oral fluconazole has a greater impact on its drug interactions with intravenous calcineurin inhibitors than intravenous fluconazole. Monitoring of blood levels of intravenous calcineurin inhibitors is recommended when the route of fluconazole administration is switched from intravenous to oral. © 2007 Springer-Verlag.

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Inflluence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia of lymphoma

N. Shimasaki, T. Mori, C. Torii, R. Sato, H. Shimada, Y. Tanigawara, K. Kosaki, T. Takahashi

J. Pediatr. Hematol. Oncol. 30 （ 5 ） 347-352 2008年

研究論文（学術雑誌）, 共著, 査読有り

小児深在性真菌症患者におけるmicafunginの有効性，安全性および薬物動態

砂川慶介，月本一郎，豊永義清，恒松由記子，岩井直一，谷川原祐介

日本化学療法学会雑誌 56 （ 2 ） 190-201 2008年

研究論文（学術雑誌）, 単著, 査読有り

呼吸器感染症に対するsitafloxacinの一般臨床試験

齋藤　厚，谷川原祐介，渡辺　彰，青木信樹，二木芳人，河野　茂，賀来満夫，堀　誠治，戸塚恭一

日本化学療法学会雑誌 56 （ S1 ） 63-80 2008年

研究論文（学術雑誌）, 共著, 査読有り

MRSA感染症患者に対するarbekacin 200mg１日１回投与の治療効果－臨床薬理試験－

相川直樹，河野　茂，賀来満夫、渡辺　彰，山口恵三，谷川原祐介

日本化学療法学会雑誌 56 （ 3 ） 299-312 2008年

研究論文（学術雑誌）, 共著, 査読有り

Population pharmacokinetics of landiolol hydrochloride in healthy subjects

Honda Naoki, Nakade Susumu, Kasai Hidefumi, Hashimoto Yoshitaka, Ohno Tomoya, Kitagawa Junsaku, Yamauchi Akinori, Hasegawa Chihiro, Kikawa Shinichi, Kunisawa Takayuki, Tanigawara Yusuke, Miyata Yasuyuki

Drug Metabolism and Pharmacokinetics 23 （ 6 ） 447 - 455 2008年

ISSN 1347-4367

Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting β₁-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.

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慢性呼吸器病変の二次感染患者を対象としたgarenoxacinの臨床第Ⅲ相試験-PK/PD試験-

小林　宏行，谷川原　祐介，渡辺　彰，青木　信樹，佐野　靖之，小田切　繁樹，二木　芳人，河野　茂，斎藤　厚

日本化学療法学会雑誌 55 （ SUPPL. 1 ） 144 - 161 2007年10月

ISSN 1340-7007

The efficacy and safety of garenoxacin mesilate hydrate(GRNX), new oral des-fluoroquinolone antimicrobial, were investigated in patients with secondary infection occurred on chronic respiratory disorders. Patients were treated with GRNX 400 mg once daily for 10 days. Plasma concentration of GRNX in each patient was determined and the obtained clinical results were analysed based on pharmacokinetics(PK) and pharmacokinetics/pharmacodynamics(PK/PD) parameters. Clinical efficacy rates were 87.8% (108/123) at the end of treatment and 83.7% (103/123) at the 7th day of post-treatment. Bacteriological eradication rates were 89.6% (60/67) and 85.1% (57/67) at the above time points. Eradication rates of causative organisms were 100% (13/13) in Streptococcus pneumoniae, 7/8 in Staphylococcus aureus, 100% (28/28) in Haemophilus influenzae and 8/8 in Moraxella (Branhamella) catarrhalis at the end of treatment. All penicillin-resistant S. pneumoniae(PRSP) including penicillin-intermediate resistant S. pneumoniae(PISP) were eradicated. Drug-related adverse events were observed in 19 patients (26 events), the incidence rate was 14.0% (19/136). Gastrointestinal disorders including 4 cases of diarrhea (2.9%), 3 of loose stool (2.2%) and 3 of vomiting (2.2%) were frequently observed. Laboratory abnormalities were observed in 26 patients (19.3%). Frequent abnormalities were 14 cases of AST elevation (10.4%), 13 of ALT elevation (9.6%) and 5 of serum amylase elevation (3.8%). No relationship was observed between PK parameters (AUC_0-24 and Cmax) and incidence of adverse events. 90.9% of patient in this study exceeded the target value of fAUC_0-24/MIC > 50. Clinical efficacy at the 7th day of post-treatment was 91.7% (55/60) in those cases whose target value was more than 50, but it was only 3/6 in those whose target value was less than 50. Similar results were obtained in studies in US and EU. From aboves, it indicates that GRNX is a beneficial antimicrobial agent for secondary infection of chronic respiratory diseases.

Phase II study of oxaliplatin in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines

Boku Narikazu, Ohtsu Atsushi, Hyodo Ichinosuke, Shirao Kuniaki, Miyata Yoshinori, Nakagawa Kazuhiko, Tamura Takao, Hatake Kiyohiko, Tanigawara Yusuke

Japanese Journal of Clinical Oncology 37 （ 6 ） 440 - 445 2007年06月

ISSN 0368-2811

Background: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m² every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. Methods: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m² every 3 weeks. Results: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1 - 6). The overall response rate was 9% (5/57, 95% CI: 4 - 19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. Conclusions: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients. © 2007 Foundation for Promotion of Cancer Research.

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がん化学療法レジメンのエビデンスとなる臨床論文の副作用特性に基づいた「副作用グレード評価シート」の作成

今村知世, 後田奈緒美, 津田壮一郎, 谷川原祐介

日本病院薬剤師会雑誌 43 （ 6 ） 796-799 2007年06月

研究論文（学術雑誌）, 単著

ロラタジンシロップの小児における通年性アレルギー性鼻炎に対する第Ⅲ相二重盲検比較試験－フマル酸ケトチフェンドライシロップに対する非劣性の検討－

石川哮，谷川原祐介，鈴木五男，上埜光紀，橋本紘治，熊井惠美，宗信夫，中島光好

臨床医薬 23 （ 11 ） 965 - 990 2007年

Reversal effects of Ca2+ antagonists on multidrug resistance via down-regulation of MDR1 mRNA.

Komoto Chiho, Nakamura Tsutomu, Yamamori Motohiro, Ohmoto Nobuko, Kobayashi Hironao, Kuwahara Akiko, Nishiguchi Kohshi, Takara Kohji, Tanigawara Yusuke, Okamura Noboru, Okumura Katsuhiko, Sakaeda Toshiyuki

The Kobe journal of medical sciences 53 （ 6 ） 355 - 363 2007年

In previous reports, the effects of 12 Ca2+ antagonists on a multidrug resistant transporter, P-glycoprotein/MDR1, were evaluated in terms of those on MDR1-mediated transport of [3H]digoxin and the sensitivity of vinblastine sulfate or paclitaxel, and they were able to be classified into 4 subgroups based on their actions, as those with transport inhibition and sensitivity recovery, those with or without transport inhibition but marginal sensitivity recovery, and those without both. In this study, our previous findings were confirmed by the resistance against doxorubicin hydrochloride and daunorubicin hydrochloride, and by the recovery of [3H] vinblastine sulfate accumulation. Furthermore, it was found that the effects of 12 Ca2+ antagonists on the sensitivity recovery were also explained by the down-regulation of MDR1 mRNA, suggesting a novel mechanism to reverse the MDR1-mediated multidrug resistance.

ロラタジンドライシロップの小児アトピー性皮膚炎に対する第Ⅲ相二重盲検比較試験－フマル酸ケトチフェンドライシロップに対する非劣性の検討－

川島眞，谷川原祐介，鈴木五男，原田昭太郎，中川秀巳，古江増隆，久木田淳，中島光好

臨床医薬 23 （ 11 ） 991 - 1016 2007年

Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors

Yamada Yasuhide, Tamura Tomohide, Yamamoto Noboru, Shimoyama Tatsu, Ueda Yutaka, Murakami Haruyasu, Kusaba Hitoshi, Kamiya Yoshikazu, Saka Hideo, Tanigawara Yusuke, McGovren J. Patrick, Natsumeda Yutaka

Cancer Chemotherapy and Pharmacology 58 （ 2 ） 173 - 182 2006年08月

ISSN 0344-5704

Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m². Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m² dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C_max values of 103 ± 17 ng/ml at the 13 mg/m² dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression ≥50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m². The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m². The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors. © Springer-Verlag 2005.

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Phase I study of single-dose oxaliplatin in Japanese patients with malignant tumors

Shirao Kuniaki, Matsumura Yasuhiro, Yamada Yasuhide, Muro Kei, Gotoh Masahiro, Boku Narikazu, Ohtsu Atsushi, Nagashima Fumio, Sano Yasushi, Mutoh Manabu, Tanigawara Yusuke

Japanese Journal of Clinical Oncology 36 （ 5 ） 295 - 300 2006年05月

ISSN 0368-2811

Background: Oxaliplatin, a platinum compound, has been commonly used around the world for treating advanced colorectal cancer. The generally recommended dose and schedule of oxaliplatin monotherapy is 130 mg/m² every 3 weeks. This trial was conducted to evaluate the safety and pharmacokinetics of oxaliplatin monotherapy in Japanese patients with solid tumors. Methods: Oxaliplatin was administered as a 2-h intravenous infusion every 3 weeks at a dose of 90 and 130 mg/m². Blood was collected to determine the total platinum and the ultrafiltrate platinum concentrations in plasma in all cycles. Results: Nine patients were enrolled; three were given oxaliplatin monotherapy at 90 mg/m² and six received 130 mg/m². All tumors were colorectal cancer. The major adverse reactions included myelosuppressive, neurological and gastrointestinal toxicities, although most were grades 1 and 2 at both dose levels. Peripheral sensory neuropathy of without movement disturbance (grade 1 or 2) was observed in all patients at both dose levels. The 130 mg/m² dose level was not found to be the maximum tolerated dose, but was judged to be the recommended dose. No objective responses were seen and five cases of no change were observed. A bi-exponential open model best described the disappearance of platinum in the plasma, and a tri-exponential open model best described the disappearance of ultrafilterable platinum in the plasma at both dose levels. No racial difference was suggested in the pharmacokinetics of oxaliplatin. Conclusions: The oxaliplatin monotherapy dose schedule of 130 mg/m² every 3 weeks, recommended worldwide, is acceptable for Japanese patients. © 2006 Oxford University Press.

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Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) As first-line therapy for patients with colorectal cancer

Yamada Yasuhide, Ohtsu Atsushi, Boku Narikazu, Miyata Yoshinori, Shimada Yasuhiro, Doi Toshihiko, Muro Kei, Muto Manabu, Hamaguchi Tetsuya, Mera Kiyomi, Yano Tomonori, Tanigawara Yusuke, Shirao Kuniaki

Japanese Journal of Clinical Oncology 36 （ 4 ） 218 - 223 2006年04月

ISSN 0368-2811

Background: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. Methods: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m²) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m²) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m² (level 1) to 500 mg/m² (level 2). Results: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. Conclusions: Oxaliplatin (85 mg/m²) with weekly bol us 5-FU (400 mg/m²) and high-dose l-LV (250 mg/m²) is recommended for further phase III studies in patients with metastatic colorectal cancer. © 2006 Oxford University Press.

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Thalidomide for the treatment of leptomeningeal multiple myeloma

Hattori Yutaka, Yabe Mariko, Okamoto Shinichiro, Morita Kunihiko, Tanigawara Yusuke, Ikeda Yasuo

European Journal of Haematology 76 （ 4 ） 358 - 359 2006年04月

ISSN 0902-4441

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Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma

Shimasaki Noriko, Mori Tetsuya, Samejima Hazuki, Sato Reiko, Shimada Hiroyuki, Yahagi Naohisa, Torii Chiharu, Yoshihara Hiroki, Tanigawara Yusuke, Takahashi Takao, Kosaki Kenjiro

Journal of Pediatric Hematology/Oncology 28 （ 2 ） 64 - 68 2006年02月

ISSN 1077-4114

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m²), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate. Copyright © 2006 by Lippincott Williams & Wilkins.

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Population Pharmacokinetic Analysis of Micafungin in Japanese Patients with Fungal Infections

谷川原祐介

Drug Metab. Pharmacokinet. 21 （ 4 ） 324-331 2006年

研究論文（学術雑誌）, 単著

1173C>T polymorphism in VKORC1 modulates the required warfarin dose

K. Kosaki, C. Yamaghishi, R. Sato, H. Semejima, H. Fuijita, K. Tamura, K. Maeyama, H. Yamagishi, A. Sugaya, H. Dodo, Y. Tanigawara, T. Takahashi

Pediatr. Cardiol. 27 （ 6 ） 685-688 2006年

研究論文（学術雑誌）, 共著, 査読有り

Novel application of proteinchip technology exploring acute rejection markers of rat small bowel transplantation

Yamayoshi Yasuko, Watanabe Toshihiko, Tanabe Minoru, Hoshino Ken, Matsumoto Koshi, Morikawa Yasuhide, Shimadzu Motohide, Kitajima Masaki, Tanigawara Yusuke

Transplantation 82 （ 3 ） 320 - 326 2006年

ISSN 0041-1337

BACKGROUND. Because no biomarker that reflects small bowel allograft rejection is available, we applied surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to develop noninvasive markers required for routine diagnosis. METHODS. Heterotopic small bowel transplantation (SBT) was performed in rats, and they were divided into four experimental groups: sham-operated rats (sham), syngeneic transplants (syngeneic), allogeneic transplants (allogeneic), allogeneic transplants received FK506 (allo+FK). Plasma samples were analyzed with SELDI ProteinChip arrays to detect peaks that predominated in the allogeneic model. Possible biomarkers were identified in combination with SELDI retentate chromatography mass spectrometry (RCMS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The identified protein was further analyzed by immunohistochemistry. RESULTS. An increase in the level of a 14.8-kDa protein, identified as lysozyme, was observed specifically in the plasma of the allogeneic group; the levels of this protein remained unchanged in the plasma of the other groups. On the other hand, the levels of a 10.1-kDa and a 13.0-kDa protein, identified as migration inhibitory factor-related proteins (MRP), MRP-8 and MRP-14, respectively, began to increase from an early stage of acute rejection. We also observed that lysozyme-positive macrophages had strongly infiltrated the lamina propria during acute rejection. CONCLUSIONS. We identified three plasma proteins-MRP-8, MRP-14, and lysozyme-that increased during small bowel allograft rejection. The identified proteins appeared to be markers for inflammation associated with allograft rejection. This proteomic approach will be useful for the identification of candidate biomarkers. Copyright © 2006 by Lippincott Williams & Wilkins.

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Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections

Tabata Kenji, Katashima Masataka, Kawamura Akio, Tanigawara Yusuke, Sunagawa Keisuke

Biological and Pharmaceutical Bulletin 29 （ 8 ） 1706 - 1711 2006年

ISSN 0918-6158

The objective of this study was to propose the appropriate dosage regimen of micafungin for pediatric use, considering the effects of dose-linearity, age and other cofactors on the pharmacokinetics. Pharmacokinetic analysis of micafungin and its active metabolites (M1 and M2) after intravenous infusion at doses of 1 to 3 mg/kg was conducted for 19 Japanese pediatric patients (3 infants, 7 toddlers, and 9 pupils) with deep mycosis caused by either Aspergillus or Candida species. One patient was given the maximum dose of 6 mg/kg. The Cmax of micafungin increased in proportion to the dose. The mean values (S.D.) were 5.03 (2.33), 10.25 (4.45), 14.8 (5.52) and 21.1 μg/ml at 1, 2 , 3 and 6 mg/kg, respectively. These parameters were comparable to those seen in adults when the parameter was normalized by body weight. The elimination half life (t_1/2) of micafungin over the dose range was apparently constant with the value of 13.1 h. There was no difference between the age groups observed. In fact, the metabolite concentrations were almost the same as those obtained for non-pediatric patients. Thus, micafungin showed the same dose-proportional pharmacokinetics in pediatric patients as it did in adults. No age dependent pharmacokinetics were observed in this study. It was concluded that the body weight adjustment was adequate for the treatment of micafungin in pediatric patients. © 2006 Pharmaceutical Society of Japan.

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Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

谷川原祐介

Antimicrobial Agents Chemother. 50 （ 11 ） 3763-3769 2006年

研究論文（学術雑誌）, 単著

Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus Aureus

谷川原祐介

Antimicrobial Agents Chemother. 50 （ 11 ） 3754-3762 2006年

研究論文（学術雑誌）, 単著

A New Active Vitamin D,ED-71, Increases Bone Mass in Osteoporotic Patients under Vitamin D Supplementation:A randomized, Double-Blind, Placebo-Controlled Clinical Trial

Toshio Matsumoto, Takami Miki, Hiroshi Hagino, Toshitsugu Sugimoto, Sumiaki Okamoto, Takako Hirota, Yusuke Tanigawara, Yasufumi Hayashi, Masao Fukunaga, Masataka Shiraki, and Toshitaka Nakamura,'

J. Clin. Endocrinol. Metab. 90 （ 9 ） 5031-5036 2005年09月

研究論文（学術雑誌）, 共著

Faropenem(ファロム錠®）の健常成人と感染症患者における母集団薬物動態

Hirooka Hideki, Sou Masahiro, Miyata Koji, Shiba Kohya, Tanigawara Yusuke

臨床薬理 36 （ 4 ） 197 - 207 2005年07月

ISSN 0388-1601

Faropenem (FRPM) is an oral penem antibacterial medicine with a high stability to beta-lactamase which has a broad antibacterial spectrum and a strong antibacterial activity to gram positive bacteria, and gram negative bacteria, except for Pseudomonas aeruginosa and anaerobic bacteria. The sale of faropenem was started in 1997. Based on the plasma faropenem concentration vs. time data obtained from clinical trials using healthy adult volunteers and patients, and a post-marketing clinical study using advanced age patients, the population pharmacokinetic analysis of a total of 20 studies was performed. The concentration data of 1,065 points from 218 patients whose creatinine clearances were measured (85 points/12 patients) or estimated (980 points/206 patients) from plasma concentration levels was used for the analysis. A one-compartment model with first-order absorption was used as a pharmacokinetic model where the absorption lag-time was assumed. Among the population pharmacokinetic parameters, the apparent total body clearance (CL), apparent distribution volume (V), first-order absorption rate constant (k_a) and absorption lag-time (t_lag) showed great inter-subject variation. In the final model, creatinine clearance (CLcr) was chosen as the most influential covariate against CL and CL was well correlated with CLcr when CLcr was less than 80 mL/min. The inter-subject variability in CL was explained by considering CLcr as a cofactor. The apparent distribution volume increased in the geriatric patients. Both k_a and t_lag were dependent on meals in all patients. Based on these results, the population pharmacokinetic model of faropenem was made by taking these covariates into consideration. From the results of population pharmacokinetics analysis, the prolongation of the elimination half-life (t_1/2) of faropenem was suggested in the patients with decreased kidney function as previously reported.

Comprehensive screening of the thiopurine methyltransferase polymorphisms by denaturing high-performance liquid chromatography

Udaka Toru, Torii Chiharu, Takahashi Daisuke, Mori Tetsuya, Aramaki Michihiko, Kosaki Rika, Tanigawara Yusuke, Takahashi Takao, Kosaki Kenjiro

Genetic Testing 9 （ 2 ） 85 - 92 2005年06月

ISSN 1090-6576

The drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathiopurine, which are used as immunosuppressants and in the treatment of acute lymphoblastic leukemia and rheumatoid arthritis. TPMT enzymatic activity is a polymorphic trait, and poor metabolizers may develop life-threatening bone marrow failure. To avoid such adverse effects, the TPMT enzymatic activity in patients' red blood cells (RBCs) is routinely measured prior to thiopurine administration in a limited number of oncology clinics. In the present study, we took advantage of a highly sensitive and specific automated denaturing high-performance liquid chromatography (dHPLC) technique that not only detects known polymorphic alleles, but also identifies previously uncharacterized sequence variants. We developed a dHPLC-based protocol to analyze the entire coding region and validated the protocol to detect all 16 previously described variant alleles. We further analyzed the entire coding region of the TPMT gene in 288 control samples collected worldwide and identified two novel amino acid substitutions Arg163Cys (487C>T) and Arg226Gln (677G>A) within exons 7 and 10, respectively. The clinical application of this comprehensive screening system for examining the entire TPMT gene would help to identify patients at risk for bone marrow failure prior to 6-mercaptopurine therapy. © Mary Ann Liebert, Inc.

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がん性疼痛に対して0.1％モルヒネ軟膏が有効であった症例

栗林淳也，小杉志都子，橋口さおり，津崎晃一，武田純三，川北智子，須山郁子，木村理恵子、村松　博，谷川原祐介

ペインクリニック 26 （ 12 ） 1676-1679 2005年

研究論文（学術雑誌）, 共著, 査読有り

血液透析患者におけるテイコプラニンの至適投与法の検討

門川俊明，浅井昌樹，森田邦彦，熊谷祐生，谷川原祐介，林　松彦，猿田享男法

透析会誌 38 （ 3 ） 205 - 211 2005年

Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or subtenon injection

Inoue Makoto, Takeda Kayoko, Morita Kunihiko, Yamada Masakazu, Tanigawara Yusuke, Oguchi Yoshihisa

American Journal of Ophthalmology 138 （ 6 ） 1046 - 1048 2004年12月

ISSN 0002-9394

To compare vitreous concentrations of triamcinolone acetonide (TA) achieved by prior therapeutic intravitreal and subtenon injections. Interventional case series. Vitreous samples were collected from patients who required vitreous surgery, six having received a subtenon injection of TA and another six, an intravitreal injection. Vitreous concentrations of TA were measured by high-performance liquid chromatography. Vitreous concentrations of TA after intravitreal injection were 1.22 ± 0.24 μg/ml, significantly higher than those after subtenon injection (<0.001 μg/ml, P =. 003). Vitreous concentrations of TA after subtenon injection and TA-assisted vitrectomy performed in a few patients to visualize the transparent vitreous gel were 0.20 ± 0.11 μg/ml, an intermediate amount between these two groups. Much higher vitreous concentrations of TA after intravitreal injection than subtenon injection may accelerate therapeutic effect when intravitreal injections are given to reduce macular edema. Subtenon injections of TA may act via the sclera as opposed to the vitreous. © 2004 by Elsevier Inc. All rights reserved.

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A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam

Kosaki Kenjiro, Tamura Kazuyo, Sato Reiko, Samejima Hazuki, Tanigawara Yusuke, Takahashi Takao

Brain and Development 26 （ 8 ） 530 - 534 2004年12月

ISSN 0387-7604

N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations (∼35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs. © 2004 Elsevier B.V. All rights reserved.

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生体部分肝移植の薬理ゲノミクスならびに臨床薬理学的研究に基づくシクロスポリンの至適投与法の開発

森田邦彦，早川智久，池谷　修，野本麻衣子，三原　潔，星野　健，田辺　稔，阿部雄太，河地茂行，若林　剛，島津元秀，森川康英，北島政樹，谷川原祐介

今日の移植 17 （ 6 ） 798-800 2004年11月

研究論文（学術雑誌）, 共著

院内製剤0.05%シクロスポリン点眼液の安定性と有用性の検討

村松博, 我妻秀和, 森田邦彦, 谷川原祐介

日本病院薬剤師会雑誌 40 （ 10 ） 1273 - 1276 2004年10月

共著

Pharmacokinetic comparison of an angiotensin II receptor antagonist, telmisartan, in Japanese and western hypertensive patients using population pharmacokinetic method

S. Tatami, N. Yamamura, A. Sarashina, CL Yong, T. Igarashi, Y. Tanigawara

Drug. Metab. Pharmacokinet. 19 （ 1 ） 15-23 2004年

研究論文（学術雑誌）, 共著, 査読有り

ベンジルアルコールを除去した硝子体内投与用トリアムシノロンアセトニド溶液の作成

井上　真, 植竹美香, 武田香陽子, 磯上一成, 村松博, 山口雅也, 森田邦彦, 谷川原祐介, 山田昌和, 小口芳久

眼紀 55 （ 6 ） 445-449 2004年

研究論文（学術雑誌）, 共著

Phorbol myristate acetate stimulates degradation of a structural analogue of platelet-activating factor to a neutral lipid in human leukemic K562 Cells: Relevance to the release of lipids

T. Tsutsumi, A. Tokumura, M. Yamaguchi, S. Kitazawa, Y. Tanigawara

Biol. Pharm. Bull. 27 （ 1 ） 24-28 2004年

研究論文（学術雑誌）, 共著, 査読有り

A randomized phase II clinical trial of tailored CPT-11+S-1 vs S-1 in patients with advanced or recurrent gastric carcinoma as the first line chemotherapy

Y. Takahashi, J. Sakamoto, T. Takeuchi, M. Mai, T. Kubota, M. Kitajima, Y. Tanigawara, Y. Komatsu, T.Toge, S. Saji

Jpn. J. Clin. Oncol. 34 （ 6 ） 342-345 2004年

研究論文（学術雑誌）, 共著, 査読有り

Relationship between pharmacokinetic parameters and occurrence of adverse events in clinical trials performed in Europe and United States for an angiotensin II receptor antagonist, telmisartan

S. Tatami, A. Sarashina, N. Yamamura, T. Igarashi, Y. Tanigawara

Drug. Metab. Pharmacokinet. 19 （ 1 ） 24-32 2004年

研究論文（学術雑誌）, 共著, 査読有り

Pharmacokinetics and pharmacodynamics of meropenem in patients with severe infections（PDFなし）

森田邦彦，島田　雅彦，小林　芳夫，谷川原　祐介

Therapeutic drug monitoring 25 （ 4 ） 527 2003年08月

研究論文（研究会，シンポジウム資料等）, 共著

Excelによるバルプロ酸（バレリン）投与設計プログラムの開発

笠井英史，寺内嘉章，藤井敏彦，谷川原祐介

ＴＤＭ研究 20 （ 3 ） 257-262 2003年07月

研究論文（学術雑誌）, 共著, 査読有り

Phase I and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors

Yamamoto Noboru, Tamura Tomohide, Kamiya Yoshikazu, Ono Hiroyuki, Kondoh Hitoshi, Shirao Kuniaki, Matsumura Yasuhiro, Tanigawara Yusuke, Shimada Yasuhiro

Japanese Journal of Clinical Oncology 33 （ 6 ） 302 - 308 2003年06月

ISSN 0368-2811

Background: KRN5500, a novel spicamycin derivative, shows an inhibitory effect on protein synthesis. This phase I study was aimed at investigating the toxicity, maximum tolerated dose (MTD) and pharmacokinetics of this compound. Patients and methods: Patients with solid tumors not amenable to standard forms of treatment were eligible. KRN5500 was administered as a 2 h intravenous infusion every 4 weeks at doses of 3, 6, 10, 15 and 21 mg/m². Pharmacokinetic evaluation was performed at the first cycle. Results: Eighteen patients with advanced solid tumors were enrolled. A total of 26 cycles of KRN5500 were administered. The major toxicities were nausea, vomiting, diarrhea, fatigue and a mild reversible prolongation of prothrombin time. Grade 4 pulmonary toxicity (interstitial pneumonitis) was observed in one patient at a dose level of 15 mg/m². Severe fatigue was observed in one patient at a dose level of 21 mg/m² and the duration of fatigue tended to increase with the dose of KRN5500. Nausea and vomiting were frequently observed and became prolonged with increasing dose of KRN5500. These toxicity profiles were identified as unacceptable and further dose escalation above 21 mg/m² was withheld. The MTD was therefore determined as 21 mg/m². The peak plasma concentration and the area under the concentration-time curve of KRN5500 increased proportionally to the dose, suggesting linear pharmacokinetics. No objective antitumor response was observed. Conclusion: KRN5500, a structurally novel protein synthesis inhibitor, warrants further investigation to overcome these toxicity profiles and improve its efficacy. © 2003 Foundation for Promotion of Cancer Research.

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小児科領域感染症におけるmeropenemの臨床的検討

豊永義清，砂川慶介，本廣　孝，岩井直一，谷川原祐介，遠藤廣子，佐藤吉壮，黒木春郎，皆川真規，石和田稔彦，田島　剛，岩田　敏，長　秀男，砂押　渉，加藤達夫，番場正博，若宮英司，杉田久美子，山崎　剛，川村尚久，春田恒和，古川正強，岡田隆滋，藤本　保，石原高信，安藤昭和，津村直幹

日本化学療法学会雑誌 51 （ 12 ） 762-781 2003年

研究論文（学術雑誌）, 共著, 査読有り

Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in heealthy volunteers and hypertensive patients

谷川原祐介

Drug Metabol. Pharmacokin. 18 （ 3 ） 203-211 2003年

研究論文（学術雑誌）, 共著, 査読有り

Comparison of the pharmacokinetics of S-1, an oral anticancer agent, in Western and Japanese patients

E. Comets, K. Ikeda, P. Hoff, P. Fumoleau, J. Wanders, Y. Tanigawara

J. Pharmacokin. Pharmacodyn. 30 （ 4 ） 257-283 2003年

研究論文（学術雑誌）, 共著, 査読有り

本邦における抗MRSA薬arbekacinを中心とした使用実態

清水喜八郎，相川直樹，谷川原祐介，賀来満夫，今栄雅文，西澤宣典，中村　洋

日本化学療法学会雑誌 51 （ 11 ） 717-730 2003年

研究論文（学術雑誌）, 共著, 査読有り

MDR1-Mediated interaction of digoxin with antiarrhythmic or antianginal drugs

Kakumoto Mikio, Takara Kohji, Sakaeda Toshiyuki, Tanigawara Yusuke, Kita Tomoko, Okumura Katsuhiko

Biological ＆ pharmaceutical bulletin 25 （ 12 ） 1604-1607 2002年12月

研究論文（学術雑誌）, 共著

成人生体肝移植におけるネオーラル投与の実際

河地茂行，島津元秀，若林剛，田辺稔，星野健，長崎和仁，渋谷慎太郎，森川康英，森田邦彦，谷川原祐介，北島政樹

今日の移植 15 （ 6 ） 591-593 2002年11月

研究論文（学術雑誌）, 共著

がん性疼痛における麻薬製剤の特徴と服薬指導（PDFなし）

梨本恭子，前田宇貴，谷川原祐介，武田純三

ペインクリニック 23 （ 9 ） 1214-1221 2002年09月

研究論文（学術雑誌）, 共著

生体肝移植例におけるネオーラルの薬物動態モニタリング（PDFなし）

河地茂行，島津元秀，若林剛，田辺稔，星野健，長崎和仁，渋谷慎太郎，森川康英，森田邦彦，谷川原祐介，北島政樹

今日の移植 15 （ 5 ） 523-525 2002年09月

研究論文（学術雑誌）, 共著

Thalidomide for the treatment of refractory multiple myeloma : association of plasma concentrations of thalidomide and angiogenic growth factors with clinical outcome

Kakimoto Tsunayuki, Hattori Yutaka, Okamoto Shinichiro, Sato Norihide, Kamata Tamihiro, Yamaguchi Masaya, Morita Kunihiko, Yamada Taketo, Takayama Nobuyuki, Uchida Hideo, Shimada Naoki, Tanigawara Yusuke, Ikeda Yasuo

Japanese journal of cancer research 93 （ 9 ） 1029-1036 2002年09月

研究論文（学術雑誌）, 共著

N-Acetyltransferase 2 genotype-related sulfapyridine acetylation and its adverse events

Tanigawara Yusuke, Kita Tomoko, Aoyama Nobuo, Gobara Manabu, Komada Fusao, Sakai Toshiyuki, Kasuga Masato, Hatanaka Hisakatsu, Sakaeda Toshiyuki, Okumura Katsuhiko,

Biological & pharmaceutical bulletin 25 （ 8 ） 1058-1062 2002年08月

研究論文（学術雑誌）, 共著

Interaction of digoxin with antihypertensive drugs via MDR1

Takara Kohji, Kakumoto Mikio, Tanigawara Yusuke, Funakoshi Junko, Sakaeda Toshiyuki, Okumura Katsuhiko

Life Sciences 70 （ 13 ） 1491 - 1500 2002年02月

ISSN 0024-3205

The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK₁ cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [³H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [³H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK₁ cells, suggesting that [³H]digoxin was a substrate for MDR1. Most of the Ca²⁺ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [³H]digoxin. α-Blocker doxazosin and β-blocker carvedilol also inhibited transcellular transport of [³H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT₁ angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin. © 2002 Elsevier Science Inc. All rights reserved.

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Digoxinと高血圧治療薬との相互作用

大本暢子，谷川原祐介，角本幹夫，船越順子，高良恒史，中村任，栄田敏之，平井みどり，奥村勝彦

TDM研究 19 （ 1 ） 58-64 2002年01月

研究論文（学術雑誌）, 共著

Effects of 12 Ca²⁺ antagonists on multidrug resistance, MDR1-mediated transport and MDR1 mRNA expression

Takara Kohji, Sakaeda Toshiyuki, Tanigawara Yusuke, Nishiguchi Kohshi, Ohmoto Nobuko, Horinouchi Masanori, Komada Fusao, Ohnishi Noriaki, Yokoyama Teruyoshi, Okumura Katsuhiko

European Journal of Pharmaceutical Sciences 16 （ 3 ） 159 - 165 2002年

ISSN 0928-0987

The effects of 12 Ca²⁺ antagonists on MDR1 were examined by two independent models: the inhibitory effect on MDR1-mediated transport of [³H]digoxin using MDR1-overexpressing LLC-GA5-COL150 cell monolayers and the reversal effect on cytotoxicity of vinblastine or paclitaxel using MDR1-overexpressing Hvr100-6 cells. The inhibitory effects on [³H]digoxin transport were assessed as the 50% inhibitory concentration during 4 h exposure, and the values were the lowest for nicardipine (4.54 μM), manidipine (4.65 μM) and benidipine (4.96 μM), followed by bepridil (10.6 μM), barnidipine (12.6 μM), efonidipine (13.0 μM), verapamil (13.2 μM) and nilvadipine (18.0 μM). The reversal effect on cytotoxicity was assessed by the 50% growth inhibitory concentration after 3 days exposure, and the resistance to vinblastine or paclitaxel in Hvr100-6 cells was reversed by manidipine, verapamil, benidipine, barnidipine, and nicardipine, in that order. Bepridil, barnidipine, efonidipine, verapamil and nilvadipine showed similar inhibitory effects on [³H]digoxin transport, but barnidipine and verapamil showed a stronger effect in reversal of cytotoxicity. Real-time quantitative RT-PCR assay indicated a decrease in MDR1 mRNA expression by barnidipine and verapamil. It is concluded that Ca²⁺ antagonists cannot only be direct inhibitors of MDR1 but that some may at the same time act as inhibitors of expression of MDR1 via down-regulation of MDR1 mRNA. © 2002 Elsevier Science B.V. All rights reserved.

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高齢者におけるfaropenem sodiumの体内動態ならびに安全性の検討

柴　孝也，加治木　章，原田泰子，原田　進，高本　正祇，宮崎三弘，小山　優，山田陽介，千田　守，山本俊信，鈴木幹三，谷川原祐介

日本化学療法学会雑誌 50 （ 10 ） 640-645 2002年

研究論文（学術雑誌）, 共著, 査読有り

Simvastatin and lovastatin, but not pravastatin, interact with MDR1

Sakaeda T., Takara K., Kakumoto M., Ohmoto N., Nakamura T., Iwaki K., Tanigawara Y., Okumura K.

Journal of Pharmacy and Pharmacology 54 （ 3 ） 419 - 423 2002年

ISSN 0022-3573

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, was compared with simvastatin and lovastatin from the viewpoint of susceptibility to interaction with or via the multidrug transporter, MDR1 (P-glycoprotein). This was carried out using the MDR1-overexpressing cell line LLC-GA5-COL150, established by transfection of MDR1 cDNA into porcine kidney epithelial LLC-PK₁ cells, and [³H]digoxin, which is a well-documented substrate for MDR1. Pravastatin, at 25-100 μM, had no effect on the transcellular transport of [³H]digoxin whereas simvastatin and lovastatin suppressed the basal-to-apical transport of [³H]digoxin and increased the apical-to-basal transport. It was suggested that recognition by MDR1 was due to the hydrophobicity. In conclusion, simvastatin and lovastatin are susceptible to interaction with or via MDR1, but pravastatin is not. This is important information when selecting the HMG-CoA reductase inhibitors for patients taking drugs that are MDR1 substrates.

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生体肝移植におけるネオーラルの使用経験と血中モニタリング

長崎和仁，島津元秀，若林剛，星野健，田辺稔，河地茂行，松本賢治，森川康英，森田邦彦，谷川原祐介，北島政樹

今日の移植 14 （ 6 ） 751-752 2001年11月

研究論文（学術雑誌）, 共著

Dose-finding phase I study of simultaneous weekly infusion with doxorubicin and docetaxel in patients with advanced breast cancer

Ito Yoshinori, Aiba Keisuke, Horikoshi Noboru, Saotome Takashi, Irie Tetsuya, Sugiyama Katsuki, Nakane Minoru, Hashimoto Daigo, Yoshida Nobuyuki, Mizunuma Nobuyuki, Takahashi Syunji, Tanigawara Yusuke

International Journal of Clinical Oncology 6 （ 5 ） 242-247 2001年10月

研究論文（学術雑誌）, 共著

Identification of N-Acetyltransferase 2 and CYP2C19 Genotypes for Hair, Buccal Cell Swabs,or Fingernails Compared With Blood

Tanigawara Yusuke, Kita Tomoko, Hirono Maki, Sakaeda Toshiyuki, Komada Fusao, Okumura Katsuhiko

Therapeutic Drug Monitoring 23 （ 4 ） 341-346 2001年08月

研究論文（学術雑誌）, 共著

Phase I study of intravenous PSC-833 and doxorubicin

Minami H., Ohtsu T., Fujii H., Igarashi T., Itoh K., Uchiyama-Kokubu N., Aizawa T., Watanabe T., Uda Y., Tanigawara Y., Sasaki Y.

Japanese Journal of Cancer Research 92 （ 2 ） 220 - 230 2001年

ISSN 0910-5050

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations ≤1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m² doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m², respectively. Thirty-one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC₅₀ of P-glycoprotein expressing 8226/Dox₆ in patients' serum was decreased from 5.9 to 1.3 μg/ml (P<0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3±13.7 (mean±SD) liter/h/m², which was lower than the 49.0±16.9 liter/h/m² without PSC-833 (P<0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m², not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

Influence of sugar chain on fibrin affinity of recombinant t-PA

Aoki Shoichi, Shimizu Norihide, Shimonishi Manabu, Kitagawa Masaru, Okumura Kazuo, Tanigawara Yusuke

Biological and Pharmaceutical Bulletin 24 （ 3 ） 295 - 298 2001年

ISSN 0918-6158

The role of the sugar chain on the fibrin affinity property of tissue plasminogen activator (t-PA) was investigated using two variants of wild type t-PA (WT t-PA I and WT t-PA II) and mutant type t-PA (mt-PA ; Gln117 t-PA I and Gln117 t-PA II), whose sugar chains have different structures. In terms of fibrin affinity, Gln117 t-PA was higher than WT t-PA ; moreover, Type II was higher than Type I. Bindings mediated via finger domain (F mode) and kringle 2 domain (K2 mode) were distinguished using ε-amino caproic acid (EACA). Consequently, F mode and K2 mode bindings were inhibited by the sugar chains at Asn117 and 184, respectively. These results were assumed to be due to the steric hindrance of the sugar chains.

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CYP2C19 genotype related effect of omeprazole on intragastric pH and antimicrobial stability

Kita Tomoko, Tanigawara Yusuke, Aoyama Nobuo, Hohda Takashi, Saijoh Yoshie, Komada Fusao, Sakaeda Toshiyuki, Okumura Katsuhiko, Sakai Toshiyuki, Kasuga Masato

Pharmaceutical Research 18 （ 5 ） 615 - 621 2001年

ISSN 0724-8741

Purpose. A combination of proton pump inhibitors and antimicrobials has been applied as an anti-Helicobacter pylori (H. pylori) therapy. Omeprazole, one of the proton pump inhibitors, is metabolized by CYP2C19, which exhibits genetic polymorphism. It was reported previously that the overall anti-H, pylori efficacy can be related to the CYP2C19 genotype. The main aim of the present study was to obtain a rational explanation for the relationship between the overall anti-H. pylori efficacy and the CYP2C19 genotype. Methods. Six healthy volunteers were classified as extensive metabolizers and poor metabolizers, according to their CYP2C19 genotypes. Plasma concentrations and intragastric pH were monitored prior to and until 24 h after the administration of 20 mg omeprazole. The stability of amoxicillin, clarithromycin, and metronidazole was examined using buffer solutions with monitored intragastric pH, and their remaining percentage in the intragastric space was simulated. Results. The poor metabolizers, classified by the CYP2C19 geno-types, showed the higher effectiveness in anti-H pylori therapy, via the higher plasma concentration of omeprazole and the higher intragastric pH, and possibly the higher stability of antimicrobials in the higher intragastric pH. Conclusions. CYP2C19 genotyping is a very useful method to determine the effective and safe dosage regimen including the selection of the dual and triple therapy in anti-H. pylori therapy.

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N-acetyltransferase2 genotype correlated with isoniazid acetylation in Japanese tuberculous patients

Kita Tomoko, Tanigawara Yusuke, Chucazawa Shinji, Hatanaka Hisakatsu, Sakaeda Toshiyuki, Komada Fusao, Iwakawa Seigo, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 24 （ 5 ） 544 - 549 2001年

ISSN 0918-6158

Isoniazid (INH) is metabolized by polymorphic N-acetyltransferase2 (NAT2). In the present study, the relationship between the NAT2 genotype and the INH acetylator phenotype was examined in Japanese tuberculous patients and compared with healthy subjects. Subjects were classified according to the genotyping into NAT2* 5B (allele4), NAT2*6A (allele3) and NAT2*7B (allele2), using the PCR-RFLP method. Twelve healthy subjects and 7 tuberculous patients participated in the INH acetylator phenotyping study, in which each subject was administered an oral dose of INH, followed by urine sampling for 24 h. Urinary concentrations of INH and N-acetylisoniazid (AcINH) were measured by the HPLC method. The urinary recoveries of INH (% of dose) in healthy subjects in relation to NAT2 genotyping were as follows: 6.4±2.2 in the homozygotes for the wild-type allele, 10.7±2.2 in the compound heterozygotes for the mutant allele, and 38.6±6.4 in the homozygotes for the mutant allele. In the patients study, the findings in the corresponding three groups were 4.0±1.7, 8.8 and 18.3±9.3. Although no significant difference was found because of the lower systemic exposure of INH in patients compared with healthy subjects, there were differences in the disposition kinetics of INH between subjects with and without mutations in the NAT2 gene, and these findings were observed not only in healthy subjects but also in patients who had comedicated drugs and hepatic dysfunctions. The findings indicated that the metabolism of INH by NAT2 is clearly impaired in subjects with mutations in the NAT2 gene, and thus genotyping for three NAT2 point mutations was adequate to predict the metabolism of INH in Japanese tuberculous patients as well as healthy subjects. This NAT2 genotyping could become a useful alternative to TDM for INH.

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CYP2C19 genotype and pharmacokinetics of three proton pump inhibitors in healthy subjects

Sakai Toshiyuki, Aoyama Nobuo, Kita Tomoko, Sakaeda Toshiyuki, Nishiguchi Kohshi, Nishitora Yukari, Hohda Takashi, Sirasaka Daisuke, Tamura Takao, Tanigawara Yusuke, Kasuga Masato, Okumura Katsuhiko

Pharmaceutical Research 18 （ 6 ） 721 - 727 2001年

ISSN 0724-8741

Purpose. To predict the CYP2C19 genotype-dependence in anti-Helicobacter pylori (H. pylori) therapy when lansoprazole or rabeprazole was used instead of omeprazole as a proton pump inhibitor (PPI). Methods. A comparative pharmacokinetic study with each PPI was designed as an open, randomized, and crossover study of 18 Japanese healthy volunteers who were classified into the homozygous, heterozygous extensive metabolizer and the poor metabolizer based on the CYP2C19 genotype determined by PCR-RFLP method. Each subject received a single oral dose of 20 mg omeprazole, 30 mg lansoprazole, or 20 mg sodium rabeprazole, with at least 1 week washout period between treatments. Plasma concentrations of PPIs and their metabolites were monitored until 12 h after medication. Results. Pharmacokinetic profiles of omeprazole and lansoprazole were well correlated with the CYP2C19 genotype. The heterozygous extensive metabolizer was slightly different from the homozygote, but there was no statistically significant difference. The CYP2C19 genotype dependence found for lansoprazole was not obvious compared with omeprazole. As for rabeprazole, the pharmacokinetic profile was independent of the CYP2C19 genotype. Conclusions. CYP2C19 genotype dependence will be found in the anti-H. pylori therapy even when lansoprazole is used as the PPI.

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Factors influencing the prediction of steady state concentrations of digoxin

Nakamura Tsutomu, Kakumoto Mikio, Yamashita Kazuhiko, Takara Kohji, Tanigawara Yusuke, Sakaeda Toshiyuki, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 24 （ 4 ） 403 - 408 2001年

ISSN 0918-6158

The prediction error in the Bayesian analysis program for digoxin was evaluated in Japanese patients, and factors influencing the accuracy were investigated. Serum concentrations of digoxin were monitored two times and were compared with the predicted values obtained by using the Bayesian analysis program. The prediction error at the first time was 43.1%. Although this estimation error was reasonably restored at the second time of monitoring, the prediction error remained at 26.6%. These data suggested that unknown factors not included in the program affected the serum concentration of digoxin. Retrospective research of the digoxin serum concentrations in the patients suggested the coadministration of the drugs, which were the P-glycoprotein modulators, as well as the unexpected alteration of the serum creatinine, were the important factors influencing the prediction of the drug serum concentrations. We next examined the inhibitory effect of quinidine, verapamil and spironolactone on the transcellular transport of digoxin by using human P-glycoprotein overexpressing LLC-GA5-COL150 cells. Quinidine, verapamil and spironolactone could inhibit the transcellular transport of digoxin by 50%. In addition, the reduction of the renal clearance by 50%, which could possibly be caused by this inhibition, led to the increase of 36% in the steady state through concentrations of digoxin in the physiological pharmacokinetic model. In conclusion, the prediction of long-term serum concentration-time profiles of digoxin, based on the Bayesian analysis, will be disturbed by the coadministration of the P-glycoprotein modulators and the unexpected alteration of the serum creatinine.

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Population pharmacokinetic modeling and model validation of a spicamycin derivative, KRN5500, in phase 1 study

Takama H., Tanaka H., Sudo T., Tamura T., Tanigawara Y.

Cancer Chemotherapy and Pharmacology 47 （ 5 ） 404 - 410 2001年

ISSN 0344-5704

Purpose: KRN5500, a novel spicamycin derivative, shows the greatest activity against a human tumor xenograft model and the highest therapeutic index among spicamycin derivatives. KRN5500 is currently under clinical development in Japan and the United States. The objective of this study was to develop a population pharmacokinetic model that describes the KRN5500 plasma concentration versus time data. Methods: Data were collected from 18 patients entered in a phase 1 study. These patients received KRN5500 3-21 mg/m² as a 2-h infusion. A total of 219 concentration measurements were available. The data were analyzed using the nonlinear mixed effect model (NONMEM) program. In addition, the basic and final population pharmacokinetic models were evaluated using bootstrapping resampling. Results: The basic model selected was a two-compartment model with a combination of additive and constant coefficient of variation error models. The basic model fitted well not only the original data, but also 100 bootstrap replicates generated from the original data set. With regard to the effect of covariates selected by generalized additive modeling analysis, gender (SEX) and performance status were found to be possible determinants of the volume of central compartment by NONMEM analysis. The final regression model for V1 was V1 = θ_V1(1 - SEX × θ_SEX), where V1 is the typical population value of the volume of central compartment, and SEX = 0 if the patient is male, otherwise SEX = 1. The final model was fitted to the 200 bootstrapped samples. The mean parameter estimates were within 15% of those obtained with the original data set. Conclusions: The KRN5500 plasma concentration versus time data obtained from the phase 1 study were well described by the population pharmacokinetic model. Further evaluation by bootstrapping showed that the population pharmacokinetic model was stable.

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Influence of N-terminal peptide and oligosaccharide on the clearance of t-PA

Aoki Shoichi, Shimizu Norihide, Koyama Jun Ichi, Kato Yoshiko, Kitagawa Masaru, Okumura Kazuo, Tanigawara Yusuke

Biological and Pharmaceutical Bulletin 23 （ 4 ） 477 - 481 2000年04月

ISSN 0918-6158

We have studied the influence of Gly-Ala-Arg peptide at the N-terminus and the oligosaccharide at Asn184 on the clearance of tissue plasminogen activator (t-PA). In order to intensify the influence of these structural features, Gln117 t-PA, which is a mutant tissue plasminogen activator (mt-PA) expressed in mouse C127 cells, was used for the investigation. It is altered to remove a high mannose type oligosaccharide by the mutation of an amino acid from Asn117 to Gln. We isolated 4 variants of Gln117 t-PA by cation- exchange chromatography, which are abbreviated as S-I, S-II, L-I and L-II. These variants originated from the heterogeneity of the peptide chains (S- chain, 527 amino acids, L-chain, 530 amino acids) and oligosaccharide (Type I, 2 oligosaccharides, Type II, 1 oligosaccharide). Pharmacokinetics of these variants were investigated after single intravenous administration to male rats at a dose of 250 μg/kg. Significant differences in pharmacokinetic parameters were observed among these variants, but there was no considerable difference in fibrin clot lysis time (FCLT) activity. Gly-Ala-Arg peptide at the N-terminus increased the CL(t), whereas the oligosaccharide at Asn184 decreased the CL(t). Moreover, the effects of the N-terminal peptide and the oligosaccharide on the CL(t) were independent of each other. Our study with Gln117 t-PA revealed the role of the N-terminal peptide found in the L-chain produced during the processing of t-PA precursor.

Nicardipine and itraconazole inhibited transcellular transport of digoxin

Takara Kohji, Tanigawara Yusuke, Komada Fusao, Nishiguchi Kohshi, Sakaeda Toshiyuki, Okumura Katsuhiko

Pharmacy and Pharmacology Communications 6 （ 4 ） 167 - 171 2000年04月

ISSN 1460-8081

The inhibitory effects of nicardipine, nifedipine and itraconazole on P- glycoprotein-mediated transport of [³H]digoxin were examined using LLC-PK₁ and LLC-GA5-COL150 cells, a porcine kidney epithelial LLC-PK₁ cell line transformed with MDR1 cDNA from man which results in overexpression of P- glycoprotein on the apical membrane. Basal-to-apical transport of [³H]digoxin in LLC-GA5-COL150 cells was higher than in LLC-PK₁ cells; apical-to-basal transport was markedly lower in LLC-PK₁ cells and even lower in LLC-GA5-COL150 cells. This is consistent with the possibility that [³H]digoxin is transported by P-glycoprotein. Co-administration of nicardipine or itraconazole markedly inhibited the basal-to-apical transport of [³H]digoxin in LLC-GA5-COL150 cells, and apical-to-basal transport also increased. The effect of nifedipine was less marked than that of nicardipine or itraconazole. Intracellular accumulation of [³H]digoxin after apical application in LLC-GA5-COL150 cells was 2.3 times less than in LLC-PK₁ cells, and was increased by the addition of nicardipine or itraconazole, consistent with their inhibitory effects on transcellular transport. Following basal application of [³H]digoxin, its intracellular accumulation in LLC-GA5-COL150 cells was, unexpectedly, comparable with that in LLC-PK₁ cells, and was hardly affected by the addition of nicardipine or itraconazole. In conclusion, it has been shown that nicardipine and itraconazole inhibited transport of digoxin, which is presumably mediated by P-glycoprotein. This explains their effects observed in clinical use.

The Nobel Anticancer Drug KRN5500 Interacts with,but is Hardly Transported by Human P-Glycoprotein

Takara Kohji, Tanigawara Yusuke, Komada Fusao, Nishiguchi Kohshi, Sakaeda Toshiyuki, Okumura Katsuhiko

Japanese Journal of Cancer Research 91 248-254 2000年02月

研究論文（学術雑誌）, 共著

日本人におけるアルベカシン薬物動態の母集団パラメータ解析

芝崎茂樹，三富奈由，松元隆，森下亘通，松野恒夫，藤井広久，谷川原祐介，奥村勝彦

TDM研究 17 （ 1 ） 47-53 2000年

研究論文（学術雑誌）, 共著

Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers

Aoyama N., Tanigawara Y., Kita T., Sakai T., Shirakawa K., Shirasaka D., Kodama F., Okumura K., Kasuga M.

Journal of Gastroenterology 34 （ SUPPL. 11 ） 80 - 83 1999年12月

ISSN 0944-1174

Omeprazole is widely used for the treatment of Helicobacter pylori infection. It is metabolized by cytochrome P450 2C19 enzyme (CYP2C19) in the liver. Because this enzyme exhibits a genetic polymorphism, patients with low metabolic activity (poor metabolizers) may be exposed to higher concentrations of this drug than are patients who are extensive metabolizers. Eighty-six patients with cultured H. pylori-positive gastritis or peptic ulcers who completed the treatment and assessment of anti-H. pylori therapy were analyzed for CYP2C19 genotyping using a ploymerase chain reaction-restriction fragment length polymorphism method [the wild-type or two mutant genes (m1 in exon 5 and m2 in exon 4), or both]. Patients were classified into three groups according to the H. pylori eradication regimen: group I (n = 21; omeprazole 40 mg/day and amoxicillin 2000 mg/day for 1 week); group II (n = 21; group I regimen plus sucralfate 4000 mg/day, for 1 week); group III (n = 44; group I regimen plus clarithromycin 800 mg/day, for 1 week). The combination of two mutant alleles (m1/m1, m1/m2, m2/m2-poor metabolizers) was observed in 13 of 86 patients (15), and all poor metabolizer patients achieved H. pylori eradication regardless of their treatment regimens. In addition, the eradication rates of the poor metabolizers were significantly higher than those of other genotypes who carry homozygous or heterozygous normal allele (extensive metabolizers) in group I or groups I and II combined. CYP2C19 genotyping can provide a new strategy to choose an optimal regimen, and this genotyping is especially useful for Japanese, as the frequency of poor metabolizers is five times greater than that found among Caucasians.

Interaction of Docetaxel ('Taxotere') with Human P-Glycoprotein

Shirakawa Katsuro, Takara Kohji, Tanigawara Yusuke, Aoyama Nobuko, Kasuga Masato, Komada Fusao, Sakaeda Toshiyuki, Okumura Katsuhiko

Japanese Journal of Cancer Research 90 （ 12 ） 1380-1386 1999年12月

研究論文（学術雑誌）, 共著

Cellular Pharmacokinetics Aspects of Reversal Effect of Itraconazole on P-Glycoprotein-Mediated Resistance of Anticancer Drugs

Takara Kohji, Tanigawara Yusuke, Komada Fusao, Nishiguchi Kohshi, Sakaeda Toshiyuki, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 22 （ 12 ） 1355-1359 1999年12月

研究論文（学術雑誌）, 共著

CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori

Tanigawara Yusuke, Aoyama Nobuo, Kita Tomoko, Shirakawa Katsuro, Komada Fusao, Kasuga Masato, Okumura Katsuhiko

Clinical Pharmacology and Therapeutics 66 （ 5 ） 528-534 1999年11月

研究論文（学術雑誌）, 共著

Effects of Secretable SOD Delivered by Genetically Modified Cells on Xanthine/Xanthine Oxidase and Paraquat-Induced Cytotoxicity in Vitro

Komada Fusao, Nishiguchi Kohshi, Tanigawara Yusuke, Iwakawa Seigo, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 22 （ 8 ） 846-853 1999年08月

研究論文（学術雑誌）, 共著

Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK-603, a new antirheumatic agent in rats

Tagawa Yoshihiko, Miwa Kiyoshi, Tsukuda Ryoichi, Yoshimura Yoshinobu, Tanayama Shigeharu, Tanigawara Yusuke

Drug Metabolism and Disposition 27 （ 4 ） 495-501 1999年04月

研究論文（学術雑誌）, 共著

Possible factor for nonlinear pharmacokinetics of TAK-603, a new antirheumatic agent, in rats

Tagawa Yoshihiko, Miwa Kiyoshi, Yamashita Kenji, Tsukuda Ryoichi, Yoshimura Yoshinobu, Tanayama Shigeharu, Tanigawara Yusuke

Biopharmaceutic and Drug Disposition 20 （ 1 ） 11-18 1999年01月

研究論文（学術雑誌）, 共著

TDX, IMXによる血中ジゴキシン濃度測定における問題点

槇本博雄，喜多知子，船越順子，西口工司，駒田富佐夫，谷川原祐介，奥村勝彦

TDM研究 16 （ 1 ） 56-62 1999年01月

研究論文（学術雑誌）, 共著

Effects of Cu, Zn-superoxide dismutase delivered by genetically modified skin fibroblasts on cold-induced skin edema in rats

Nishiguchi Kohshi, Komada Fusao, Tanigawara Yusuke, Sakai Yumiko, Iwakawa Seigo, Okumura Katsuhiko

Biological and Pharmaceutical Bulletim 21 （ 12 ） 1379-1381 1998年12月

研究論文（学術雑誌）, 共著

Inhibitory effects of cyclosporin derivative, SDZ PSC833, on transport of doxorubicin and vinblastine via human P-glycoprotein

Kusunoki Nobuya, Takara Kohji, Tanigawara Yusuke, Yamauchi Aiko, Ueda Kazumitsu, Komada Fusao, Yonson Ku, Kuroda Yoshikazu, Saitoh Yohichi, Okumura Katsuhiko

Japanese Journal Cancer Research 89 （ 11 ） 1220-1228 1998年11月

研究論文（学術雑誌）, 共著

Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human α₁-acid glycoprotein

Fuse Eiichi, Tanii Hiromi, Kurata Noriaki, Kobayashi Hiroyuki, Shimada Yasuhiro, Tamura Tomohide, Sasaki Yasutsuna, Tanigawara Yusuke, Lush Richard D., Headlee Donna, Figg William D., Arbuck Susan G., Senderowicz Adrian M., Sausville Edward A., Akinaga Shiro, Kuwabara Takashi, Kobayashi Satoshi

Cancer Research 58 （ 15 ） 3248 - 3253 1998年08月

ISSN 0008-5472

The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human α₁-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to α₁-acid glycoprotein.

新規インスリンカートリッジ製剤の含量均一性についてのバリデーション

駒田富佐夫，大道るみ，畑中久勝，谷川原祐介，奥村勝彦

薬剤学 58 （ 3 ） 164-169 1998年06月

研究論文（学術雑誌）, 共著

Cross-reactivity of TDX and OPUS immunoassay systems for serum digoxin determination

Okazaki Mamie, Tanigawara Yusuke, Kita Tomoko, Komada Fusao, Okumura Katsuhiko

Therapeutic Drug Monitoring 19 （ 6 ） 657 - 662 1997年12月

ISSN 0163-4356

The properties of the widely used TDX Analyzer and recently developed OPUS Immunoassay System were compared using 403 serum specimens taken from patients who did or did not take digoxin. Of the 210 specimens from patients not treated with digoxin, a false-positive digoxin concentration was detected in 15 specimens (7%) by TDX and in only 2 specimens (1%) by OPUS because of the cross-reactivity with structurally similar drugs. Potassium canrenoate, digitoxin, deslanoside, and methyldigoxin exhibited marked concentration- dependent cross-reactivity in the TDX assay method, whereas deslanoside and methyldigoxin only showed cross-reactivity with the antibody used in the OPUS method. Although a poor correlation was observed between these two methods for the determination of 193 samples from patients treated with digoxin, the correlation was remarkably improved (r = 0.914) and the slope approximated unity when excluded the data from patients who were treated concurrently with the cross-reactive compounds. In routine TDM of digoxin, the authors experienced two cases in which cross-reactivity of the assay system caused a clinical problem. Concurrent administration of intravenous canrenoate apparently interfered with the digoxin assay by TDX, but this problem was solved by using the OPUS system. The authors found OPUS more useful for monitoring serum digoxin concentrations in patients because of its superior specificity.

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Genotyping of N-acetylation polymorphism and correlation with procainamide metabolism

Okumura Katsuhiko, Kita Tomoko, Chikazawa Shinji, Komada Fusao, Iwakawa Seigo, Tanigawara Yusuke

Clinical Pharmacology and Therapeutics 61 （ 5 ） 509 - 517 1997年05月

ISSN 0009-9236

We studied the genotypes of polymorphic N-acetyltransferase (NAT2) in 145 Japanese subjects by the polymerase chain reaction-restriction fragment length polymorphism method. The rapid-type NAT2*4 was expressed at a higher frequency (68.6%) than the slow-type genes with specific point mutations (NAT2*6A, 19.3%; NAT2*7B, 9.7%; NAT2*5B, 2.4%). The frequency of NAT2* genotypes consisted of 44% of a homozygote of NAT2*4, 49% of a heterozygote of NAT2*4 and mutant genes, and 7% of a combination of mutant genes. The metabolic activity for procainamide to N-acetylprocainamide was measured in 11 healthy subjects whose genotype had been determined. Although the acetylation activity substantially varied interindividually, the variability was considerably reduced after classification according to the genotype. The N-acetylprocainamide/procainamide ratio in urinary excretion was 0.60 ± 0.17 (mean ± SD) for those with NAT2*4/*4, 0.37 α 0.06 for NAT2*4/*6A, 0.40 ± 0.03 for NAT2*4/*7B, and 0.17 for NAT2*6A/*7B. The results indicated that the NAT2* genotype correlates with acetylation of procainamide.

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Protective effect of transfection with secretable superoxide dismutase (SOD) (a signal sequence-SOD fusion protein coding cDNA) expression vector on superoxide anion-induced cytotoxicity in vitro

F. Komada, K. Nishiguchi, Y. Tanigawara, M. Ishida, X.-Y. Wu, S. Iwakawa, R. Sasada, K. Okumura

Biol. Pharm. Bull 20 （ 5 ） 530 - 536 1997年05月

Relationship between expression level of P-glycoprotein and daunorubicin transport in LLC-PK₁ cells transfected with human MDR1 gene

Tanaka Kumiko, Hirai Midori, Tanigawara Yusuke, Ueda Kazumitsu, Takano Mikihisa, Hori Ryohei, Inui Ken Ichi

Biochemical Pharmacology 53 （ 5 ） 741 - 746 1997年03月

ISSN 0006-2952

P-Glycoprotein-mediated transcellular transport and intracellular accumulation of [³H]daunorubicin were examined in cell monolayers with different levels of P-glycoprotein. The porcine kidney epithelial cell line LLC-PK₁ was transfected with MDR1 cDNA, and four sublines, LLC-GA5, LLC-GA5-VLB4, LLC-GA5-COL10, and LLC-GA5-COL150, were obtained by culturing the cells in the absence or in the presence of 4 ng/mL vinblastine, 10 ng/mL colchicine, and 150 ng/mL colchicine, respectively. Western blot analysis showed a large difference in P-glycoprotein expression within these sublines. The degree of drug resistance was dependent on the expression level of P-glycoprotein. The amount of the unidirectional transport of [³H]daunorubicin by P-glycoprotein corresponded to the expression level of P-glycoprotein, which was followed by the decrease in intracellular accumulation of the agent. The concentration of cyclosporin A required for the inhibition of P-glycoprotein-mediated transport of [³H]daunorubicin was higher in cells with a high expression of P-glycoprotein. These findings suggest that the transport of daunorubicin by P-glycoprotein and its inhibition by cyclosporin A correspond to the expression level of P-glycoprotein.

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Pharmacokinetics of Adriamycin and cisplatin for anhepatic chemotherapy during liver transplantation

Ku Yonson, Kusunoki Nobuya, Kitagawa Tetsushi, Maeda Ichiro, Fukumoto Takumi, Iwasaki Takeshi, Tominaga Masahiro, Suzuki Yasuyuki, Kuroda Yoshikazu, Tanigawara Yusuke, Saitoh Yoichi

Cancer Chemotherapy and Pharmacology 40 （ 6 ） 457 - 462 1997年

ISSN 0344-5704

We investigated the pharmacokinetics of cytotoxic anticancer agents administered under anhepatic conditions. Beagle dogs underwent either a sham operation consisting of laparotomy only (control group, n = 11) or a laparotomy and total hepatectomy under venovenous bypass (anhepatic group, n 12). Each dog received a bolus intravenous injection of either Adriamycin (1 mg/kg) or cisplatin (1 mg/kg). The plasma and urine concentrations of each drug were measured at intervals for up to 2 h after drug injection. The dogs given Adriamycin were then sacrificed to determine tissue drug concentrations in the liver (controls only), spleen, kidney, heart, lung, skeletal muscle and small intestine. The control and anhepatic groups showed similar Adriamycin profiles during the initial 5 min after drug injection. However, subsequently, the plasma Adriamycin concentrations remained persistently higher in the anhepatic dogs than in the controls, yielding a two-fold elevation of the mean area under the concentration-time curve in the anhepatic group (P<0.01 vs controls). The renal clearance values did not significantly differ between the two groups. The tissue Adriamycin concentrations in all measured organs, excluding the liver, were higher in the anhepatic group than in the controls. In a second set of experiments with cisplatin, the plasma platinum concentrations did not significantly differ between the two groups throughout the time course. However, the renal clearance of platinum in the anhepatic dogs showed a fourfold increase compared with that in the controls (P<0.01). These pharmacokinetics data suggest that Adriamycin carries the risk of increased systemic toxicities, while cisplatin may be associated with increased renal toxicity when administered during the anhepatic period of liver transplantation.

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Enhanced anti-inflammatory effects of Cu, Zn-superoxide dismutase delivered by genetically modified skin fibroblasts in vitro and in vivo

Okumura Katsuhiko, Nishiguchi Kohshi, Tanigawara Yusuke, Mori Sachiko, Iwakawa Seigo, Komada Fusao

Pharmaceutical Research 14 （ 9 ） 1223 - 1227 1997年

ISSN 0724-8741

Purpose. The purpose of this work was to evaluate the anti-inflammatory effects of secretable human Cu, Zn-superoxide dismutase (hSOD) delivered by genetically modified skin fibroblasts in vitro and in vivo. Methods. Rat skin fibroblasts were transfected with pRc/CMV-ILSOD including secretable SOD-coding cDNA. The effects of host and transformants on oxidative stress in vitro models using the xanthine/xanthine oxidase (X/XO) system were examined to study the paracrine SOD action. The anti-inflammatory effects by transplantation of host and transformants were evaluated in an acute inflammation model, carrageenin-induced paw edema, in rats. Results. The transformants (ILSOD cells) secreted SOD protein into the extracellular space, and the extracellular SOD activity in ILSOD cells cultures was significantly increased compared with that in host cell cultures. ILSOD cells diminished the cytotoxic activity by X/XO in a paracrine fashion. These protective effects of ILSOD cells against X/XO-induced cytotoxicity correlated well with the decrease in lipid peroxidation in the damaged cells. The in vivo study showed that transplantation of ILSOD cell suspensions into the hind paw in rats inhibited carrageenin-induced paw edema for at least 7 days, and the degree and the durability of these inhibitory effects were dependent on the number of ILSOD cells transplanted. These inhibitory effects of ILSOD cell suspensions were reduced by co-administration of antiserum for hSOD. Furthermore, the healing of paw edema caused by carrageenin was markedly enhanced by transplantation of ILSOD cells into the edemics hind paw. Conclusions. The findings suggested that genetically modified skin fibroblasts are a suitable delivery system for obtaining an efficient and continuous supply of SOD to the target site, and this strategy may be a useful drug delivery system for therapeutic proteins.

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ヒト二相性イソフェンインスリン水性懸濁製剤の含量均一性についてのバリデーション

駒田　富佐夫，大道　るみ，畑中　久勝，谷川原　祐介，奥村　勝彦

薬剤学 57 （ 4 ） 190 - 196 1997年

肝静脈分離・活性炭吸着（HVI・CHP）による経皮的肝灌流におけるCyclosporin併用の意義

楠　信也，具　栄成，谷川原　祐介，前田　一郎，杉本　武巳，村松　三四郎，岩崎　武，富永　正寛，黒田　嘉和，斎藤　洋一

癌と化学療法 23 （ 11 ） 1408 - 1411 1996年09月

ISSN 0385-0684

It is difficult to administer an effective dose of cyclosporin A (CsA), a potent inhibitor of P glycoprotein, to prevent multiple drug resistance due to its side effect. We herein evaluated the efficacy of concomitant use of this agent and complete hepatic venous isolation and charcoal hemoperfusion (HVI·CHP). Dogs were divided into two groups: group I (n=4), intraarterial infusion of only adriamycin (ADM) and group II (n=4), intraarterial infusion of CsA and ADM. In both groups, ADM was intraarterially administered for 10 minutes under HVI·CHP. In addition, in group II, CsA infusion (0.3 mg/min · kg) was initiated 20 min prior to the start of ADM infusion and maintained for 30 min. The AUC (μg · min/ml) of ADM were 21.2 ± 8.6 (mean ± SD) and 28.4 ± 10.3 in groups I and II, respectively, at prefilter (hepatic venous level) and 8.1 ± 4.6 and 4.8 ± 3.8, respectively, at postfilter, showing an effective drug elimination in both groups. The C(max) (μg/ml) were 14.1 ± 2.2 at prefilter, 2.4 ± 0.5 at postfilter, and 3.4 ± 1.2 in systemic level. These results indicated that HVI·CHP allowed the high dose CsA infusion required for P-gp inhibition in the liver and could reduce extraregional CsA leakage.

Effect of transfection with a superoxide dismutase expression plasmid on xanthine/xanthine oxidase-induced cytotoxicity in cultured rat lung cells

Komada Fusao, Nishiguchi Kohshi, Tanigawara Yusuke, Wu Xiao Ying, Iwakawa Seigo, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 19 （ 8 ） 1100 - 1102 1996年08月

ISSN 0918-6158

We inserted human Cu, Zn-superoxide dismutase (hSOD) cDNA into the eukaryotic expression plasmid (pRc/CMV) under the control of the cytomegalovirus promoter. The hSOD expression plasmid (pRc/CMV-SOD) was transfected in L2 cells by mean of lipofection. The intracellular SOD activity in pRc/CMV-SOD transfected cells (CMV-SOD cells) was about twice that in host cells. However the level of extracellular SOD activity was similar in CMV-SOD and host cells. When exposed to xanthine (X)/xanthine oxidase (XO) to generate active oxygen species, significantly more CMV-SOD cells than host cells survived. The production of lipid peroxidation in host cells significantly increased in the presence of X/XO, but that in CMV-SOD cells did not change. Thus, transfection with SOD gene effectively prevented X/XO-induced cytotoxicity. The results indicated that increasing the level of intracellular SOD activity protected cells against extracellular superoxide anion stress.

Pharmaceutical studies for gene therapy

Nishiguchi Kohshi, Ishida Kazue, Nakajima Masanori, Maeda Tetsuo, Komada Fusao, Iwakawa Seigo, Tanigawara Yusuke, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 19 （ 8 ） 1073 - 1077 1996年08月

ISSN 0918-6158

To evaluate whether lipofection using Lipofectin(TM) is suitable for delivering foreign genes into skin fibroblasts as target cells, we performed experiments using human superoxide dismutase (hSOD) and neomycin-resistance (Neo¹) genes as models in rat skin fibroblasts (FR and primary cells) in vitro. The amounts of DNA used in the lipofection procedure significantly affected the transfection efficiencies, and the optimal amounts were determined for all cells used. However, the efficiencies in rat skin fibroblasts were about 20-fold higher than that in rat lung epithelial-like cells (L2 cells). The differences in plasmid vectors (pRc/RSV-SOD and pRc/CMV-SOD) hardly affected the transfection efficiencies. The amounts of Lipofectin(TM) significantly affected the transfection efficiencies, and the optimal amounts were determined for both types of skin fibroblasts. However, cytoxic effects in both skin fibrobalsts were observed with high doses of Lipofectin(TM). On the other hand, with optimal amounts of DNA and Lipofectin(TM), the reporter gene (Neo¹) introduced into cells was mainly integrated into the host cell chromosome. Western blot analysis showed the continuous expression of hSOD protein for at least 45 d in skin fibroblasts transfected with the expression plasmid for hSOD by Lipofectin(TM) under the optimal conditions, and the cellular SOD activity fluctuated in parallel with the expression of hSOD protein. Differences in the type of cells also affected the expression of hSOD. These results indicate that it is necessary to set up optimal conditions for transfection using Lipofection(TM) for each cell type, and that transfection with Lipofectin(TM) under optimal conditions may be an efficient method for introduction of foreign genes into skin fibroblasts for use as a clinical delivery system of therapeutic protein.

Effect of transfection with superoxide dismutase expression plasmid on superoxide anion induced cytotoxicity in cultured rat lung cells

Komada Fusao, Nishiguchi Kohshi, Tanigawara Yusuke, Akamatsu Taeko, Wu Xiao Ying, Iwakawa Seigo, Okumura Katsuhiko

Biological and Pharmaceutical Bulletin 19 （ 2 ） 274 - 279 1996年02月

ISSN 0918-6158

Human Cu, Zn-superoxide dismutase (hSOD) cDNA was inserted into a eukaryotic expression plasmid (pRc/CMV) under the control of a cytomegalovirus promoter. The hSOD expression plasmid (pRc/CMV-SOD) was transfected into L2 cells by means of lipofection. The integration of the hSOD gene in genomic DNAs in the cells transfected with pRc/CMV-SOD plasmid was examined by Southern blotting using hSOD cDNA as the probe. However, Southern blots of host cells (without transfection) and CMV cells (pRc/CMV plasmid transfection) indicated no hybridization of hSOD cDNA. Western blots indicated that hSOD was expressed in CMV-SOD cells. The SOD activity in CMV- SOD cells was about twice that in host and CMV cells. Furthermore, this SOD activity in CMV-SOD cells was enhanced for 60 d after the selection of cell clones. After exposure to paraquat and catalase, about 90% of the CMV-SOD cells survived compared with the untreated controls, whereas about 60% of the host cells survived. The production of lipid peroxidation in host cells increased significantly after exposure to both paraquat and catalase, whereas that in CMV-SOD cells did not change. The correlation between the surviving cells and lipid peroxidation was inverse. These results indicated that transfection with the SOD gene was effective against superoxide anion induced cytotoxicity.

Effects of transfection with the Cu, Zn-superoxide dismutase gene on Xanthine/xanthine oxidase-induced cytotoxicity in fibroblasts from rat skin

Nishiguchi Kohshi, Ishida Kazue, Nakajima Masanori, Maeda Tetsuo, Komada Fusao, Iwakawa Seigo, Tanigawara Yusuke, Okumura Katsuhiko

Pharmaceutical Research 13 （ 4 ） 577 - 582 1996年

ISSN 0724-8741

Purpose. The effects of transfection with the human Cu, Zn-superoxide dismutase (hSOD)⁴ gene on active oxygen-induced cytotoxicity in rat skin fibroblasts (FR) were studied for the purpose of developing the novel delivery system of hSOD using hSOD gene. Methods. An expression plasmid for hSOD, pRc/RSV-SOD, was constructed and used to transfect FR cells. Xanthine (X)/xanthine oxidase (XO) system were used to generate active oxygen species. The effects of transfection with the hSOD gene on active oxygen-induced cytotoxicity were assessed by comparing the number of surviving cells and the level of lipid peroxidation in host and transformants after exposure to X/XO system. Results. The cellular SOD activity in RSV-SOD cells transfected with pRc/RSV-SOD was significantly increased in comparison with host or RSV cells transfected with the pRc/RSV plasmid containing no hSOD gene as a control. Furthermore, Western blot analysis using an anti-hSOD antibody indicated the production of hSOD in RSV-SOD cells. On the other hand, although the numbers of surviving cells in both host and RSV-SOD cultures after exposure to X/XO system decreased in a time-dependent manner, the decrease in number of surviving RSV-SOD cells was less than that in host cells. In the presence of catalase, the decreases in number of surviving cells in both host and RSV-SOD cultures after exposure to the X/XO system were also less than those in the absence of catalase. However, the decreases in cell survival in RSV-SOD cultures were significantly less than those in host cells in the presence of catalase. Furthermore, the levels of lipid peroxidation in RSV-SOD cells exposed to the X/XO system in the presence or absence of catalase were lower than those in host cells. These results indicated that the increase in cellular SOD activity by transfection with the hSOD gene protects cells from oxidative stress. Conclusions. Human SOD gene therapy may be useful for treatment of diseases in which oxidative tissue damage is produced.

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Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P-glycoprotein

Tanaka Kumiko, Hirai Midori, Tanigawara Yusuke, Yasuhara Masato, Hori Ryohei, Ueda Kazumitsu, Inui Ken Ichi

Pharmaceutical Research 13 （ 7 ） 1073 - 1077 1996年

ISSN 0724-8741

Purpose. P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated. Methods. The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506. Results. Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity. Conclusions. In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.

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薬理動態からみた肝局所化学療法における経動脈性および経門脈性抗癌剤投与の比較

塩谷　雅文，具　英成，楠　信也，北川　哲司，前田　一郎，富永　正寛，谷川原　祐介，黒田　嘉和，斎藤　洋一

癌と化学療法 22 （ 11 ） 1560 - 1562 1995年09月

ISSN 0385-0684

We investigated the adriamycin (ADR) pharmacokinetics following intraarterial and intraportal infusion under hepatic venous isolation and charcoal hemoperfusion (HVI·CHP), HVI·CHP was used to measure the first pass amount of adriamycin through the liver and to reduce hepatic re entry of the drug. Beagles underwent a 10-min ADR infusion (1 mg/kg) either through the hepatic artery (group 1, n = 5) or the portal vein (group II, n = 5) under a 20 min HVI·CHP. During HVI·CHP, the hepatic venous flow rate and plasma ADR levels in prefilter (hepatic venous level), postfilter and peripheral blood were serially measured. Based on these measurements, the hepatic extraction ratio (HER) of ADR was calculated. Areas under the time concentration curves of prefilter levels in groups I and II were 6.1 ± 1.6 and 16.9 ± 5.0 μg · min/ml, respectively, showing a significant difference between two groups (p<0.01). On the contrary, HER of group I (81.2%) was significantly higher than that of group II (47.2%, p<0.01). These results indicate that intraarterial infusion of ADR is superior to intraportal infusion in terms of local drug delivery to the liver and systemic drug toxicities.

Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases

Tanigawara Y., Nomura H., Kagimoto N., Okumura K., Hori R.

Biological and Pharmaceutical Bulletin 18 （ 2 ） 315 - 320 1995年

ISSN 0918-6158

The population pharmacokinetics of levofloxacin (LVFX), the l-enantiomer of ofloxacin, were studied in 522 subjects, including normal subjects and patients with infectious diseases. Altogether, 1572 LVFX serum concentrations were obtained following a single oral administration during clinical trials. The influences of renal function, age, meals and concurrent drug administration on the pharmacokinetic parameters of LVEX were examined by the likelihood ratio test using a nonlinear mixed-effect model (NONMEM). In patients with renal insufficiency, the total body clearance (CL) of LVFX was related to creatinine clearance (Ccr) and body weight (WT), as expressed by CL=0.0836 Ccr+0.013 WT. The CL with normal renal function was 0.178 (l/h/kg). The apparent volume of distribution (Vd) was calculated to be 1.46 (l/kg). The elderly subjects, aged 65 years old or over, exhibited, on average, a 32% reduction in CL and 6% greater Vd. LVFX was rapidly absorbed in the gastrointestinal tract, but the concurrent administration of antacids (magnesium, aluminum, etc.) decreased the bioavailability of LVEX by 15-52%. The recommended dose of LVFX was decided on the basis of current pharmacokinetic information and the minimum inhibitory concentrations. Population pharmacokinetic parameters are also useful for the individualization of a dosage regimen by means of the Bayesian forecasting method.

Cepharanthin, a multidrug resistant modifier, is a substrate for P- glycoprotein

Hirai M., Tanaka K., Shimizu T., Tanigawara Y., Yasuhara M., Hori R., Kakehi Y., Yoshida O., Ueda K., Komano T., Inui K. I.

Journal of Pharmacology and Experimental Therapeutics 275 （ 1 ） 73 - 78 1995年

ISSN 0022-3565

P-glycoprotein modulators are respected to be multidrug resistance reversing agents in cancer chemotherapy. Some calcium channel blockers, calmodulin inhibitors or immunosuppressive agents have been used in clinical studies, although the dose of these drugs required to test in vitro experimental data might cause potent pharmacological effects which are not desirable in patients. By using LLC-GA5-COL150 cells that express P- glycoprotein specifically on the apical membranes, we examined the transport of anticancer drugs mediated by P-glycoprotein. Cepharanthin, a biscoclaurine alkaloid, potently inhibits the transport of vinblastine and daunorubicin, both commonly used anticancer agents. The 50% inhibitory concentration of cepharanthin on daunorubicin transport was 2.06 μM. Combined inhibitory effects on daunorubicin transport were observed when cepharanthin was used together with cyclosporin A, a potent immunosuppressive agent and P- glycoprotein modulator. Cepharanthin itself was transported by P- glycoprotein. Transcellular transport of cepharanthin across LLC-GA5-COL150 cell monolayers was saturable when its concentration was under 5 μM, and the transport was inhibited by P-glycoprotein modulators. These results indicate that cepharanthin can reverse multidrug resistance, and proper combination with other P-glycoprotein modulators could potentiate its inhibitory effect on expelling the anticancer drugs out of the cell via P-glycoprotein.

Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation

Tanigawara Y., Komada F., Shimizu T., Iwakawa S., Iwai T., Maekawa H., Hori R., Okumura K.

Biological and Pharmaceutical Bulletin 18 （ 11 ） 1590 - 1598 1995年

ISSN 0918-6158

The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparation. Food ingestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption. The 400-mg tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not older than 15 years showed 58% longer absorption lag time. The inter-individual variability in Ka was 19%, suggesting small variability in the in vivo release process. The total body clearance was related to hepatic function, smoking habits, and age. Furthermore, clearance decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for dose individualization based on serum concentration monitoring with or without the Bayesian feedback method.

Predictive performance of the Bayesian analysis

Tanigawara Yusuke, Yano Ikuko, Kawakatsu Kazuo, Nishimura Koichi, Yasuhara Masato, Hori Ryohei

Journal of Pharmacokinetics and Biopharmaceutics 22 （ 1 ） 59 - 71 1994年02月

ISSN 0090-466X

The present paper reports theoretical equations for the predictive performance of the Bayesian forecasting method. The precision of parameter estimates and predicted concentrations for an individual was described by general equations with the aid of a variance-covariance matrix of parameter estimates that involved the Bayes theorem. The equations were applied to assess the predictive performance of the one-point Bayesian method in association with blood sampling time, the population parameters, and the pharmacostatistical model. The simulation study showed that the prediction error in parameter estimates essentially depended upon the sampling time but the magnitude of dependency was affected by the size of inter-and intraindividual variances. With a smaller value of interindividual variance, the dependency on sampling time was less apparent. Effects of sampling time were further examined using clinical data obtained from 20 patients taking theophylline, and the results were in good agreement with the theoretical consideration. The present general equations are useful to investigate the sampling strategy as well as structural and variance modeling on the predictive performance of the Bayesian method. © 1994 Plenum Publishing Corporation.

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日本人における薬物動態母集団パラメータの推定（１）：ジゴキシン

堀　了平，宮崎　勝巳，水柿　道直，緒方　宏泰，後藤　光良，市村　藤雄，安原　眞人，谷川原　祐介，橋本　征也，小上　淑子，三牧　孝至，田中　一彦，奥村　勝彦，五味田　裕，樋口　駿

TDM研究 11 （ 1 ） 7 - 17 1994年

Renal handling of tobramycin in the isolated perfused rat kidney

Aiba T., Itoga Y., Shimizu H., Tanigawara Y., Hori R.

Journal of Pharmaceutical Sciences 83 （ 5 ） 723 - 726 1994年

ISSN 0022-3549

The renal handling of tobramycin (TOB), an aminoglycoside antibiotic (AG), was studied using a single-pass isolated perfused rat kidney with moment analysis. In the bolus administration study at tracer concentration (7.4 μM), 32% of the glomerular-filtrated TOB remained in the lumen, but no TOB was found in the vein. This ratio of the luminal uptake was reduced in a dose-dependent manner. Other aminoglycosides such as gentamicin inhibited this uptake, but tetraethylammonium and glucosamine had no effect. In addition, under the alkalinuria condition, TOB uptake was decreased to 67% of the control value. This indicated that TOB has mainly been taken into the renal epithelial cells from their luminal site and that this uptake process was saturable and specific for AGs which have more than one cationic group. The present findings should be helpful in developing a method to reduce the nephrotoxicity of AGs and to identify their toxicity mechanisms.

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バミカミドのPopulation Pharmacodynamics

寺川　雅人，伊与田　奈美，谷川原　祐介，

臨床薬理 25 （ 4 ） 603 - 613 1994年

ISSN 0388-1601

The population pharmacodynamics of vamicamide, a new anticholinergic drug, were analyzed by nonlinear mixed effect modeling (NONMEM) in 16 healthy male subjects. The subjects were given orally 18, 36 or 48 mg of vamicamide in a single- or multiple-dose regimen. Serum concentrations of vamicamide were measured frequently; the average urine flow rates (AFRs) estimated simply by dividing the urine volume by the time during voiding, were measured on each occasion of urination. Serum concentrations corresponding to the time of urination were predicted by curve-fitting the individual data (a total of 293 serum data) to a one-compartment model with first-order absorption. The serum concentration-AFR data (381 data pairs) thus obtained were used for NONMEM analysis. The Emax model with baseline controls was used for serum cncentration-AFR response data. The voided volume significantly affected not only the baseline AFR but also maximum response (Emax). However, the concentration which causes half of Emax (EC₅₀) was independent of voided volume and was estimated to be 167 ng/ml. At the serum concentration of 140 ng/ml, which is the maximum serum concentration at therapeutic standard dosage regimen, the percent reduction of AFR from the baseline value was estimated to be 32 and 38% when the voided volume is assumed to be 400 ml, respectively. Despite the wide range of variability in AFR, the NONMEM analysis provided clinically significant concentration-response curves. This population approach appears recommendable for further clinical applications.

Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients

Hashimoto Y., Odani A., Tanigawara Y., Yasuhara M., Okuno T., Hori R.

Biological and Pharmaceutical Bulletin 17 （ 2 ） 323 - 326 1994年

ISSN 0918-6158

The pharmacokinetics of zonisamide was studied using routine therapeutic drug monitoring data from 68 epileptic patients. The 266 serum concentration data at steady-state after repetitive oral administration were analyzed using the nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose- dependent clearance was used for the pharmacokinetic analysis of zonisamide. The volume of distribution (V) was estimated to be 1.27 l/kg in a typical 33- kg patient, assuming that the bioavailability of orally administered zonisamide is 100%. The maximal daily dose to be cleared (V(max)) and the concentration giving half maximal clearance (a Michaelis-Menten constant) was 27.6 mg/d/kg and 45.9 μg/ml, respectively. The parameter of a power function of weight to adjust V and V(max) was estimated to be 0.741. In addition, V(max) for zonisamide appears to be 13% increased in patients receiving carbamazepine concurrently. The population pharmacokinetic parameters of zonisamide will be useful for designing dosage regimens in epileptic patients.

マイクロパーティクルEIA法によるタクロリムスの血中濃度モニタリング

橋田　亨，池西　政幸，虎口　美典，谷川原　祐介，木邑　道夫，安原　眞人，堀　了平，上本　伸二，田中　紘一，小澤　和恵

TDM研究 11 （ 1 ） 18 - 22 1994年

P-glycoprotein-mediated transcellular transport of MDR-reversing agents

Saeki Tohru, Ueda Kazumitsu, Tanigawara Yusuke, Hori Ryohei, Komano Tohru　

FEBS Letters 324 （ 1 ） 99 - 102 1993年06月

ISSN 0014-5793

Understanding of the interactions between P-glycoprotein and multidrug resistance (MDR) reversing agents is important in designing more effective MDR modulators. We examined transcellular transport of several MDR modulators by using a drug-sensitive epithelial cell line, LLC-PK₁ and its transformant cell line, LLC-GA5-COL300, which expresses human P-glycoprotein on the apical surface. Basal-to-apical transports of azidopine and diltiazem across the LLC-GA5-COL300 monolayer were increased and apical-to-basal transports were decreased compared to those across the LLC-PK₁ monolayer, indicating that P-glycoprotein transports azidopine and diltiazem. Movements of nitrendipine and staurosporine across the epithelial monolayer were not affected by P-glycoprotein. These results suggests that some MDR modulators exert their inhibitory effect not only by blocking the initial binding of anticancer drugs but throughout the course of the transport process. © 1993.

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Human P-glycoprotein transports cyclosporin A and FK506

Saeki Tohru, Ueda Kazumitsu, Tanigawara Yusuke, Hori Ryohei, Komano Tohru

Journal of Biological Chemistry 268 （ 9 ） 6077 - 6080 1993年03月

ISSN 0021-9258

Cyclosporin A, a cyclic undecapeptide, and FK506 are efficient immunosuppressive agents. They also attract attention as effective P-glycoprotein modulators that inhibit P-glycoprotein from binding to anticancer drugs and overcome multidrug resistance. Cyclosporin A itself interacts with a common binding site of P-glycoprotein to which Vinca alkaloids and verapamil bind. We were interested to determine whether cyclosporin A and FK506 are substrates for P-glycoprotein to transport, and we studied their transcellular transport. In LLC-PK₁ cells, derived from porcine kidney proximal tubule and forming a highly polarized epithelium, cyclosporin A was transported in a saturable manner. LLC-GA5-COL300, a transformant cell line derived by transfecting LLC-PK₁ with human MDR1 cDNA isolated from normal adrenal gland, expresses P-glycoprotein specifically on the apical surface and shows a typical multidrug-resistant phenotype. LLC-GA5-COL300 cells showed increased transport of cyclosporin A from the basal to the apical side. Kinetic analysis showed that this transport was a typical saturable transport with the calculated apparent Michaelis constant (K_m^app) and the maximum flux (V_max) as 8.4 μM and 2.4 nmol/mg protein/h, respectively. LLC-GA5-COL300 also snowed increased transport of FK506 from the basal to the apical side. These results indicate that P-glycoprotein transports the immunosuppressive agents cyclosporin A and FK506.

Population pharmacokinetics of theophylline. II

Yano I., Tanigawara Y., Yasuhara M., Okumura K., Kawakatsu K., Nishimura K., Hori R.

Biological and Pharmaceutical Bulletin 16 （ 5 ） 501 - 505 1993年

ISSN 0918-6158

The population pharmacokinetics of theophylline were studied in 55 patients with stable chronic airway obstruction. Two hundred and seventy six theophylline serum concentrations after intravenous short infusion were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, smoking habit, age and the measurement of arterial blood gases (oxygen tension: PaO₂, carbon dioxide tension: PaCO₂, blood pH) and clinical laboratory tests (serum albumin concentration, haematocrit) on the pharmacokinetic parameters of theophylline was examined by the likelihood ratio test. Assessment of each factor was made by a forward selection method. In the final regression model, the total body clearance (CL, l/h/kg) was related to the value of PaCO₂ as well as to the presence of hepatic dysfunction, and the volume of distribution (V(d), l/kg) was related with the PaCO₂ value as expressed in the following equations: CL=exp(- 3.78 - 0.525. HF+ 0.0233. PaCO₂) and V(d)=exp(- l.12 + 0.00934. PaCO₂), where HF is a categorical variable with a value of unity if a patient has hepatic dysfunction otherwise zero. The interactions among blood gas measurements were observed and the CL and V(d) of theophylline would be inversely correlated with PaO₂ or pH, if we selected PaO₂ or blood pH to be a more important factor than PaCO₂. The inter-individual variabilities in CL and V(d) were 38.5% and 12.5%, respectively, and the residual variability in theophylline serum concentrations was 10.6% as a coefficient of variation. This final model and the population parameters of theophylline will be useful for individualization of a drug dosage regimen by means of the Bayesian method. Significant correlation between arterial blood gas measurements and pharmacokinetic parameters observed in this study indicates that the pharmacokinetics of theophylline can vary in association with the severity of respiratory diseases.

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney

Hori R., Okamura N., Aiba T., Tanigawara Y.

Journal of Pharmacology and Experimental Therapeutics 266 （ 3 ） 1620 - 1625 1993年

ISSN 0022-3565

The mechanism for renal tubular secretion of digoxin as well as its interaction with quinidine or verapamil were investigated using the isolated perfused rat kidney. [³H]Digoxin was instantaneously administered into the renal artery together with [¹⁴C]inulin and Evans blue-albumin, and renal venous and urinary outflow curves were measured. The ratio of fractional excretion to filtration fraction for digoxin was 2.40 ± 0.40, indicating involvement of tubular secretion. Quinidine and verapamil decreased the ratio of fractional excretion to filtration fraction in a concentration-dependent manner, and this inhibition was indicated to occur at transport from cells to lumen across luminal membranes. Neither tetraethylammonium nor p- aminohippurate affected the renal handling of digoxin. Because ouabain and digitoxose showed no influence on the value of fractional excretion to filtration fractions, Na⁺,K⁺-ATPase is not involved in the tubular secretion of digoxin. A metabolic inhibitor, 2,4-dinitrophenol, markedly inhibited digoxin secretion. Agents that bind to P-glycoprotein, such as vinblastine, daunorubicin and reserpine, markedly inhibited the secretion of digoxin. Recently, we have found that digoxin is a substrate transported by P-glycoprotein. The findings obtained here support the hypothesis that digoxin is secreted by P-glycoprotein located on the luminal membrane of renal tubular epithelial cells, and that clinically important interactions with quinidine and verapamil are caused by the inhibition of P-glycoprotein.

Digoxin-cyclosporin A interaction

Okamura N., Hirai M., Tanigawara Y., Tanaka K., Yasuhara M., Ueda K., Komano T., Hori R.

Journal of Pharmacology and Experimental Therapeutics 266 （ 3 ） 1614 - 1619 1993年

ISSN 0022-3565

The mechanism of a renal tubular digoxin-cyclosporin A interaction was elucidated using a kidney epithelial cell line and the isolated perfused rat kidney. The cells expressed an excess amount of human P-glycoprotein on the apical membranes by transfection with MDR1 cDNA. Cyclosporin A inhibited the trans-epithelial transport of digoxin mediated by human P-glycoprotein; net basal-to-apical transport across the cell monolayer was 22.8, 21.2, 6.61 and 0.91 pmol/mg of protein/3 hr in the presence of 0, 1, 5 and 10 μM cyclosporin A, respectively. Cyclosporin A also reduced the renal tubular secretion of digoxin by the kidney. The ratio of fractional excretion/filtration fraction for digoxin was 2.88 ± 0.71 (mean ± S.D.) in the control, and this was decreased to 1.21 ± 0.09 and 1.05 ± 0.13 in the presence of 1 and 5 μM cyclosporin A, respectively. Because no signs of acute nephrotoxicity were observed, a direct effect of cyclosporin A accounted for the reduced secretion. On the other hand, digoxin did not affect cyclosporin A transport by P-glycoprotein. These findings indicate that serum concentrations of digoxin in patients should be carefully monitored when administered concurrently with cyclosporin A. The present transepithelial transport system using the transfectant cells is a simple and useful screening system for predicting drug interactions that can occur in a clinical situation.

Population pharmacokinetics of theophylline. I

Yano I., Tanigawara Y., Yasuhara M., Mikawa H., Hori R.

Biological and Pharmaceutical Bulletin 16 （ 1 ） 59 - 62 1993年

ISSN 0918-6158

The population pharmacokinetics of theophylline during constant-rate intravenous infusion has been studied in 66 children (8.7 ± 4.7 year of age; 26.0 ± 12.8 kg, mean ± S.D.) with an episode of acute asthma. One hundred and twelve theophylline serum concentrations (13.9 ± 4.8 μg/ml) collected retrospectively were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, age, gender, days after admission, blood gas measurements (PaO₂, PaCO₂, blood pH) and clinical analyses data (total serum protein, albumin concentration, haemoglobin concentration, haematocrit) on theophylline clearance was examined by the likelihood ratio test. A final estimate of population mean clearance was 58.6 ml/kg/h, which was decreased by 36% in patients with hepatic dysfunction. Other factors tested displayed no statistically significant effect on theophylline clearance. The inter-individual variability in clearance was 26% while the intra-individual variability in theophylline concentrations was 2.6 μg/ml as a standard deviation, which was almost double that observed for stable patients. Taking into account that the therapeutic window of this drug is 10-20 μg/ml, this value indicates a relatively large intra-individual variability and suggests that frequent (daily) monitoring of serum concentrations is necessary for patients with an episode of acute asthma.

Human P-glycoprotein transports cortisol, aldosterone, and 　dexamethasone, but not progesterone

Ueda Kazumitsu, Okamura Noboru, Hirai Midori, Tanigawara Yusuke, Saeki Tohru, Kioka Noriyuki, Komano Tohru, Hori Ryohei

Journal of Biological Chemistry 267 （ 34 ） 24248 - 24252 1992年12月

ISSN 0021-9258

We expressed human MDR1 cDNA isolated from the human adrenal gland in porcine LLC-PK1 cells. A highly polarized epithelium formed by LLC-GA5-COL300 cells that expressed human P-glycoprotein specifically on the apical surface showed a multidrug-resistant phenotype and had 8.3-, 3.4-, and 6.5-fold higher net basal to apical transport of ³H-labeled cortisol, aldosterone, and dexamethasone, respectively, compared with host cells. But progesterone was not transported, although it inhibited azidopine photoaffinity labeling of human P-glycoprotein and increased the sensitivity of multidrug-resistant cells to vinblastine. An excess of progesterone inhibited the transepithelial transport of cortisol by P-glycoprotein. These results suggest that cortisol and aldosterone are physiological substrates for P-glycoprotein in the human adrenal cortex and that substances that efficiently bind to P-glycoprotein are not necessarily transported by P-glycoprotein.

Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK₁)

Tanigawara Y., Okamura N., Hirai M., Yasuhara M., Ueda K., Kioka N., Komano T., Hori R.

Journal of Pharmacology and Experimental Therapeutics 263 （ 2 ） 840 - 845 1992年

ISSN 0022-3565

This article represents the first evidence that the renal secretion of the commonly used drug, digoxin, is mediated by P-glycoprotein. In this study, it was demonstrated that digoxin is a substrate of P-glycoprotein, and the mechanism of a clinically important drug interaction, such as digoxin- quinidine, was elucidated. Human P-glycoprotein was expressed on the apical membrane of the porcine kidney epithelial cell line, LLC-PK₁ by transfecting with human MDR1 cDNA. The expression and function of P-glycoprotein were confirmed by Southern and Western blotting, RNase protection assay, immunostaining and transporting activity for vinblastine. The transepithelial transport of [³H]digoxin was measured across the cell monolayers grown on microporous polycarbonate membrane filters. The transfectant cells exhibited markedly greater basal-to-apical transport and less apical-to-basal transport than the host cells, and the former was 8-fold greater than the latter. The augmented transepithelial transport resulted from the increased efflux from cells to apical side. This oriented transport was inhibited by the presence of 20 μM vinblastine, quinidine or verapamil. The rate of efflux to the apical side was 2-fold greater than that to the basal side. Quinidine inhibited the efflux to the apical side but did not affect transport into the basal side. These findings demonstrate that digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney other than organic cation and anion transport systems, and suggest a molecular mechanism for the renal tubular secretion of digoxin as well as clinically important digoxin-quinidine interaction via P-glycoprotein.

Total body and hepatic clearance in rats of recombinant tissue-type plasminogen activator expressed in mouse C127 and Chinese hamster ovary cells

Hori R., He Y. L., Shima T., Inui K. I., Aoki S., Okumura K., Tanigawara Y.

Drug Metabolism and Disposition 20 （ 4 ） 541 - 546 1992年

ISSN 0090-9556

The total body and hepatic clearance of two recombinant human tissue-type plasminogen activators (t-PA) produced in mouse C127 cells [t-PA(C127)] and in Chinese hamster ovary cells [t-PA(CHO)] were determined in rats. Recombinant t-PA was administered as a constant iv or intraportal venous infusion for 60 min. The plasma t-PA level over 120 min was measured by an ELISA. Whole-body pharmacokinetics were characterized in terms of the total body clearance (CL(t)), total volume of distribution, and mean residence time in the body. Hepatic disposition was described by the hepatic clearance (CL(hep)) and the mean hepatoportal transit time. Whereas a marked hepatic extraction was observed with both-t-PAs, the estimated CL(hep) accounted for only one-half the CL(t). No elimination took place in the lung, because no difference was observed between iv and intraarterial administration. Extrahepatic elimination, such as that in circulating blood, appeared to play a significant role in the disposition of t-PA in vivo. t-PA(C127) is known to possess the Galα1-3Gal epitope in its complex-type carbohydrate chains, whereas this structure is not involved in t-PA(CHO). In the presence of Bandeiraea simplicifolia lectin I isolectin B₄, which is specific to the Galα1-3Gal, the CL(t) of t-PA(C127) was significantly decreased, whereas that of t-PA(CHO) was unchanged. These results imply that the formation of a high molecular weight complex by this carbohydrate epitope effectively reduces the rate of catabolism of t-PA in vivo.

Effect of leukotriene C₄ on theophylline disposition in guinea pigs

Tanigawara Y., Yano I., Yasuhara M., Hori R.

American Review of Respiratory Disease 146 （ 3 ） 616 - 620 1992年

ISSN 0003-0805

The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C₄ (LTC₄)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals received 5 μg/kg of LTC₄ intravenously 60 min later. The plasma theophylline concentration 30 min after LTC₄ treatment was significantly lower (p < 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the treated animals showed significantly slower declines in plasma concentrations of both drugs (0.0805 ± 0.0199 and 0.291 ± 0.020 h^-1 for theophylline and antipyrine, respectively, mean ± SEM) than did controls (0.197 ± 0.010 and 0.439 ± 0.028 h^-1). Leukotriene C₄ treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of serum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p < 0.001, 94.4 ± 3.3% in treatment versus 58.2 ± 4.4% in control), but that of antipyrine was unchanged (94.9 ± 3.0% in treatment versus 92.1 ± 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC₄ treatment, and the apparent change in the volume of distribution was estimated as 26.1 ± 5.6%. Results showed that the LTC₄ response can influence the disposition kinetics of theophylline and suggested a possible mechanism for the intraindividual variability in acutely ill patients.

Moment analysis of drug disposition in kidney. VI

He Yan Ling, Tanigawara Yusuke, Kamiya Akira, Hori Ryohei

Journal of Pharmacokinetics and Biopharmaceutics 19 （ 6 ） 667 - 690 1991年12月

ISSN 0090-466X

This paper describes a novel method to assess the antiluminal membrane (ALM) and luminal membrane (LM) transport in vivo across renal tubular epithelial cells. The method is based upon a noncompartmental moment analysis of the plasma concentration and urinary excretion rate curves following renal artery injection. Quantitative relationships are represented between the noncompartmental parameters (clearance, volume of distribution, and the mean transit time) and the first-order rate constants associated with transmembrane transport processes. The in vivo transepithelial transport of [¹⁴C]p -aminohippurate (PAH) was examined using the rat kidney in the absence or presence of various plasma concentrations of unlabeled PAH, cefazolin, and methotrexate. The tubular secretion intrinsic clearance was reduced with an increase in the plasma concentration of concurrent unlabeled organic onions. The distribution volume of PAH in the kidney decreased in association with a decrease in the amount of PAH secreted, whereas the mean transepithelial (artery-to-lumen) transit time (-T_cell) remained constant. These findings indicate that ALM transport is a capacity-limited process determining the amount of tubular secretion, and that LM transport is linear over the concentration range examined and independent of the amount of secretion. The contribution of ALM and LM transport to transcellular transport was first clarified in vivo. The present method will be useful for analyzing the transmembrane transport processes in vivo for highly diffusible substances in the kidney. © 1991 Plenum Publishing Corporation.

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Effects of counteranion of TRH and loading amount on control of TRH release from copoly(dl-lactic/glycolic acid) microspheres prepared by an in-water drying method

Toshiro Heya, Hiroaki Okada, Yusuke Tanigawara, Yasuaki Ogawa, Hajime Toguchi

International Journal of Pharmaceutics 69 （ 1 ） 69 - 75 1991年02月

ISSN 0378-5173

The preparation of injectable sustained release microspheres of TRH was investigated. The drug was encapsulated in copoly(dl-lactic/glycolic acid) (PLGA) using an in-water drying method through a w/o/w emulsion. The predominant factors influencing the entrapment ratio of TRH in the microspheres and the release rate of TRH from the microspheres were the loading amount and the dissociation state of the drug. Microspheres of TRH encapsulated as a free base at an adequate concentration provided a small initial burst followed by a zero-order prolonged release regardless of the high water solubility of the drug. The addition of strong acids to the inner aqueous phase interfered with the encapsulation efficacy and caused a large initial burst. The ionic interaction between the basic functional group of TRH and the carboxylic acid end group of PLGA during the preparation is necessary to produce a rigid matrix of the microspheres. This method is applicable to the microencapsulation of other water-soluble basic peptides in PLGA. © 1991.

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Moment analysis of drug disposition in kidney. V

Hori Ryohei, He Yan Ling, Saito Yoshihiro, Kamiya Akira, Tanigawara Yusuke

Journal of Pharmacokinetics and Biopharmaceutics 19 （ 1 ） 51 - 70 1991年02月

ISSN 0090-466X

A new method that can assess the kinetics of in vivo transepithelial transport in rat kidney has been established. The method is based upon a multiple-indicator dilution experiment and the moment analysis theory. After simultaneous bolus injections of p-aminohippurate (PAH) and inulin into the right renal artery, blood samples were taken from the carotid artery and urine was separately collected from right and left ureters. The characteristic response for the first passage of drugs through the right kidney was evaluated by taking blood circulation into consideration. To determine the mean artery-tovein transit time and the extraction ratio in the kidney, an intravenous injection was also performed as a reference experiment for deconvolution. The urinary excretion curve corresponding to the first passage was obtained as the difference between both kidneys. The mean artery-tolumen transit time (mean transepithelial transit time, -T_cell)was computed by subtracting the mean urinary transit time of inulin from that of secreted PAH. Sinc transport across the luminal membrane into the lumen from tubular epithelial cells can influence the cellular residence time of drugs, - T_celland the single-pass mean residence time in epithelial cells (-T_cell.sp)can be thought of describing luminal membrane transport. The value of -T_{cell obtained for 0. t mM PAH was 22 sec and it was prolonged to 61 sec in the presence of probenecid, suggesting an inhibitory effect on transport across the luminal membrane. On the other hand, antiluminal membrane transport into cells from blood is characterized by the volume of distribution in the kidney} (Vd_PAH). Vd_{PAH was remarkably decreased by treatment with probenecid, indicating an inhibitory effect on antiluminal membrane transport. The effects of probenecid on both sides of epithelial cell membrane transport were first demonstrated} in vivo. The present method is useful for the analysis of in vivo transepithelial transport including antiluminal and luminal membrane transport for drugs excreted via tubular secretion. © 1991 Plenum Publishing Corporation.

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Betamipronの腎毒性軽減作用とその作用機序（1）-腎組織輸送との関連-

長沼　英夫，常盤　弘，広内　康邦，川原　幸則，福重　潤一郎，深見　征治，広田　孝司，村松　重基，高萩　英邦，乾　賢一，谷川原　祐介，安原　眞人，堀　了平，桑原　章吾

Chemotherapy 39 （ SUPPL. 3 ） 166 - 177 1991年

ISSN 0009-3165

Mean residence time in organs in toxicokinetic studies

Tanigawara Y., He Y. L., Aiba T., Yasuhara M., Hori R., Hirouchi Y., Naganuma H., Kawahara Y., Okada R.

Journal of Pharmacobio-Dynamics 14 （ 2 ） 1991年

ISSN 0386-846X

Moment analysis of drug disposition in rat kidney

Saito Y., Tanigawara Y., Okamura N., Shimizu H., Kamiya A., Hori R.

Journal of Pharmacy and Pharmacology 43 （ 5 ） 311 - 316 1991年

ISSN 0022-3573

The determining step in transepithelial transport of p-aminohippurate (PAH) in renal tubular secretion has been elucidated in the rat isolated perfused kidney. The method was based upon a multiple indicator dilution experiment and non-compartmental moment analysis. Single-pass dilution curves were obtained from venous and urinary effluents after simultaneous intra-arterial injections of Evans blue with albumin, [³H]inulin and [¹⁴C]PAH. Probenecid was used as a transport inhibitor and dissolved in both perfusate and injection solution. The urinary excretion of PAH decreased depending on the probenecid concentration, while that of inulin was not affected. No correlation was observed between the amount of secretion and the mean residence time of secreted PAH in renal epithelial cells [T̄(cell)]. Since T̄(cell) ought to be affected by the rate of secretion from cells to lumen, it was suggested that the secretion rate was independent of the amount secreted. In contrast, the amount of PAH excreted via tubular secretion showed a linear correlation with the volume of distribution in the kidney and the apparent rate constant for tubular uptake of PAH. Since these kinetic parameters reflect the transport from blood into cells across the basolateral membranes of renal epithelial cells, the present results demonstrated that basolateral membrane transport is a determining step in the transcellular transport of PAH and that the major effect of probenecid is the inhibition of transport from blood into cells.

Effect of folinic acid on tissue residence and excretion of methotrexate in rats

He Y. L., Tanigawara Y., Yasuhara M., Hori R.

Drug Metabolism and Disposition 19 （ 4 ） 729 - 734 1991年

ISSN 0090-9556

The effect of folinic acid (CF) on the tissue residence and renal excretion of methotrexate (MTX) in the rat model is described in an experiment designed to resemble a clinical regimen of high-dose MTX therapy with CF rescue. Concentrations of MTX in the kidney, liver, and plasma were determined following the sequential killing of the animals up to 24 hr after an iv bolus injection of 100 μmol/kg MTX. The treated group received repeated iv doses of CF (5.86 μmol/kg) for 9.3 hr. The tissue retention property of MTX was characterized by noncompartmental parameters, the mean residence time (MRT), and the single-pass mean residence time (MRTSP) in organs. The values of MRT in the kidney and liver were greater than that in plasma and were shortened by the CF treatment, indicating that CF is effective in reducing the duration of exposure to MTX in those organs. For drugs whose duration of exposure is a key factor in their toxicity, MRTSP was shown to be a useful parameter in toxicokinetic study. The renal clearance of MTX was virtually constant over a wide range of plasma MTX levels (0.1-165 μM) and was inhibited by p-aminohippurate. CF accelerated the renal excretion of MTX, which effect depended on the plasma concentration of MTX. Since reabsorption and filtration were not affected by CF, the increased excretion of MTX was attributed to a stimulation of tubular secretion. These observations show that CF exerts a beneficial effect in accelerating the excretion of MTX residing in the organs, in addition to supplying active folate to aid the resumption of de novo DNA synthesis.

Pulmonary and hepatic disposition of hippuryl-L-histidyl-L-leucine

Tanigawara Y., He Y. L., Okumura K., Hori R.

Chemical and Pharmaceutical Bulletin 39 （ 3 ） 761 - 764 1991年

ISSN 0009-2363

Betamipronの腎毒性軽減作用とその作用機序（2）-腎排泄挙動との関連-

長沼　英夫，広内　康邦，川原　幸則，乾　賢一，谷川原　祐介，安原　眞人，堀　了平，桑原　章吾，

Chemotherapy 39 （ SUPPL. 3 ） 178 - 189 1991年

ISSN 0009-3165

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅲ.フェニトイン

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 50 （ 3 ） 292 - 299 1990年

Pharmacokinetics in chimpanzees of recombinant human tissue-type plasminogen activator produced in mouse C127 and Chinese hamster ovary cells

Tanigawara Y., Hori R., Okumura K., Tsuji J. I., Shimizu N., N oma S., Suzuki J., Livingston D. J., Richards S. M., Keyes L. D., Co uch R. C., Erickson M. K.

Chemical and Pharmaceutical Bulletin 38 （ 2 ） 517 - 522 1990年

ISSN 0009-2363

Moment analysis of drug disposition in kidney. II

Kamiya A., Tanigawara Y., Saito Y., Hayashi Y., Aiba T., Inui K., Hori R.

Journal of Pharmaceutical Sciences 79 （ 8 ） 692 - 697 1990年

ISSN 0022-3549

Effects of urine pH on the renal tubular secretion of an organic cation (tetraethylammonium, TEA) and an organic anion (p-aminohippurate, PAH) were investigated using the isolated erythrocyte-perfused rat kidney. The method was based on a multiple indicator dilution experiment and noncompartmental moment analysis. Treatment with sodium bicarbonate and sodium dihydrogen phosphate increased and decreased urine pH, respectively, but affected neither the condition of the perfused kidney nor the renal handling of albumin and inulin. In TEA studies, the increase of urine pH prolonged the mean residence time in renal epithelial cells (T̄(cell)) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vd(drug)). The decrease of urine pH did not affect these kinetic parameters. By contrast, PAH secretion was constant against the change of urine pH. Since any change in the basolateral membrane transport is reflected in Vd(drug), the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T̄(cell) of TEA with the increased urine pH suggested a slow transport from cells to lumen across the brush-border membranes. The present results coincide with the hypothelical mechanism that organic cations are secreted via an active transport system, coupled to the countertransport of H⁺ into cells. In conclusion, the present method is useful to separately evaluate the transmembrane transport across both sides of the renal epithelial cells in a morphologically intact kidney.

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Moment analysis of drug disposition in kidney. III

Tanigawara Y., Saito Y., Aiba T., Ohoka K., Kamiya A., Hori R.

Journal of Pharmaceutical Sciences 79 （ 3 ） 249 - 256 1990年

ISSN 0022-3549

A different manner of insufficiency of renal epithelial cell transport between the organic anion and cation, p-aminohippurate and tetraethylammonium, respectively, was observed in the perfused kidney isolated from uranyl nitrate-induced acute renal failure (ARF) rats. The single-pass outflow pattern of the perfused kidney was analyzed by noncompartmental moment analysis. The active tubular secretion was impaired faster than the reduction of glomerular filtration, and the tetraethylammonium secretion decreased at an earlier stage of ARF than p-aminohippurate. The apparent uptake rate constant from blood to cells of p-aminohippurate was reduced with the progress of ARF and associated with the amount of this drug secreted, whereas the uptake rate constant of tetraethylammonium did not change until the late stage of ARF. The mean residence time in renal epithelial cells of tetraethylammonium was prolonged with reduction of the amount to be secreted, while that of p-aminohippurate remained unchanged. Therefore, the uptake of p-aminohippurate across the basolateral membranes decreased gradually, and the transport across the brush border membranes was still unchanged after uranyl nitrate treatment. On the other hand, the secretion of tetraethylammonium from cells to lumen was impaired at first, and then the uptake from blood to cells was impaired. These results suggest that impairment by uranyl nitrate-induced ARF appears at the carrier-mediated transport process of the epithelial cell membranes for both organic anions and cations.

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅱ.カルバマゼピン

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 49 （ 4 ） 304 - 312 1989年

Blood oxygen tension-related change of theophylline clearance in experimental hypoxemia

Kishimoto I., Tanigawara Y., Okumura K., Hori R.

Journal of Pharmacology and Experimental Therapeutics 248 （ 3 ） 1237 - 1242 1989年

ISSN 0022-3565

The effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O₂-92% N₂. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P<.01) from 0.156 ± 0.020 l/kg/hr in control to 0.0556 ± 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.

日本人におけるPopulation Pharmacokinetic Parametersの推定　Ⅰ.バルプロ酸

堀　了平，奥村　勝彦，北澤　式文，神代　昭，齋藤　侑也，樋口　駿，水柿　道直，山路　昭，力久　忠昭，谷川原　祐介

薬剤学 49 （ 2 ） 148 - 156 1989年

Moment analysis of drug disposition in kidney

Hori R., Tanigawara Y., Saito Y., Hayashi Y., Aiba T., Okumura K., Kamiya A.

Journal of Pharmaceutical Sciences 77 （ 6 ） 471 - 476 1988年

ISSN 0022-3549

The mean renal epithelial cell residence time, T̄(cell), was defined as a model-independent characteristic of the transcellular transport process in the isolated perfused kidney. The transcellular transport process includes transport at the basolateral membrane, diffusion in the cytosol, and transport at the brush border membrane. The parameter T̄(cell) represents the mean time for the drug secreted from the tubules to pass through the renal epithelial cells, and is calculated as the difference of the mean urinary transit time between secreted drug and inulin in the single-pass perfusion system. Therefore, the urinary excretion rate-time course is indispensable to evaluate T̄(cell). p-Aminohippuric acid was used as a model compound. The bovine erythrocytes in the perfusate kept the isolated kidney in an almost constant physiological condition, including secretion function. The renal vein outflow curves were also analyzed by the use of moments. The dispersion in the cathether was corrected by a deconvolution. The apparent secretion intrinsic clearance and the apparent volume of distribution were calculated from the moments. The present method will be useful for analysis of the transcellular transport mechanism and the effect of disease states on renal transport of drugs.

腎機能障害者におけるcefixime(CFIX)の体内動態

中野　博，世古　昭三，仁平　寛巳，枡知　果夫，児玉　光人，谷川原　祐介，神谷　晃，堀　了平

Chemotherapy 36 （ 5 ） 428 - 436 1988年

ISSN 0009-3165

The design of membrane-controlled transdermal therapeutic systems containing molsidomine

Yamada M., Tanigawara Y.

Chemical and Pharmaceutical Bulletin 35 （ 8 ） 3407 - 3412 1987年

ISSN 0009-2363

Mechanism of enhancement of percutaneous absorption of molsidomine by oleic acid

Yamada M., Uda Y., Tanigawara Y.

Chemical and Pharmaceutical Bulletin 35 （ 8 ） 3399 - 3406 1987年

ISSN 0009-2363

New method for the evaluation of in vitro dissolution time and disintegration time

Tanigawara Y. Yamaoka K. Nakagawa T. Uno T.

Chem.Pharm. Bull 30 （ 3 ） 1088 - 1090 1982年

Capacity-limited elimination of cefmetazole in rat

Yamaoka K., Tanigawara Y., Nakagawa T., Uno T.

International Journal of Pharmaceutics 10 （ 4 ） 291 - 300 1982年

ISSN 0378-5173

Elimination kinetics of cefmetazole (CMZ) in the rat is studied with changing the dosing amount (D). The normalized area under plasma concentration-time curve (AUC/D) and the mean residence time (MRT) increase with increasing amount of i.v. dose of CMZ. These increases prove the capacity-limited elimination of CMZ without regard to any pharmacokinetic model. The apparent steady-state volume of distribution (V^a_ss) which is defined by D β MRT/AUC is almost independent of D. The simultaneous multi-lines fitting using time course curves following different doses is also attempted to determine the pharmacokinetic model by the application of the minimum AIC estimation (MAICE). AIC, consequently, shows the minimum for the two-compartment model with the Michaelis-Menten elimination. The Y_ss estimated from this model is about 450 ml/kg which agrees with V^a_ss estimated by moment analysis. © 1982.

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Moment analysis for the separation of mean in vivo disintegration, dissolution, absorption, and disposition time of ampicillin products

Tanigawara Y., Yamaoka K., Nakagawa T., Uno T.

Journal of Pharmaceutical Sciences 71 （ 10 ） 1129 - 1133 1982年

ISSN 0022-3549

The in vivo disintegration, dissolution, absorption, and disposition processes of ampicillin products are separated by means of moment analysis. This method is model-independent, that is, any specific model is not assumed. The mean residence time (MRT), mean absorption time (MAT), mean dissolution time (MDT), and mean disintegration time (MDIT) are calculated for several dosage forms of ampicillin. The fraction of dose absorbed (F) is also separated into several fractions corresponding to these in vivo processes. Bioavailability and bioequivalence are discussed in terms of the zero and first moments. The flip-flop behavior of ampicillin is proved by the fact that the MRT following intravenous injection is less than the MAT of any oral dosage form. Absorption of released ampicillin is proved to be a rate-determining step, since the MRT of released ampicillin in the GI tract is the greatest of all MRT corresponding to the in vivo processes. Moment analysis is compared with classical compartment theory, and a new component concept is introduced.

Correlation between in vivo mean dissolution time and in vitro mean dissolution time of ampicillin products

Tanigawara Y., Yamaoka K., Nakagawa T., Uno T.

Journal of Pharmacobio-Dynamics 5 （ 5 ） 370 - 372 1982年

ISSN 0386-846X

Absorption kinetics of carbenicillin phenyl sodium and carbenicillin indanyl sodium in man

Tanigawara Y., Yamaoka K., Nakagawa T., Uno T.

Chemical and Pharmaceutical Bulletin 30 （ 6 ） 2174 - 2180 1982年

ISSN 0009-2363

A pharmacokinetic analysis program (MULTI) for microcomputer

Yamaoka K., Tanigawara Y., Nakagawa T., Uno T.

Journal of Pharmacobio-Dynamics 4 （ 11 ） 879 - 885 1981年

ISSN 0386-846X

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