研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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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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