研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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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

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谷川原 祐介

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谷川原　祐介

論文 - 谷川原　祐介