CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers

被引：45

作者：

Fukuda T. ^{[1
]}

Onishi S. ^{[1
]}

Fukuen S. ^{[1
]}

Ikenaga Y. ^{[1
]}

Ohno M. ^{[1
]}

Hoshino K. ^{[1
]}

Matsumoto K. ^{[1
]}

Maihara A. ^{[2
]}

Momiyama K. ^{[2
]}

Ito T. ^{[3
]}

Fujio Y. ^{[1
]}

Azuma J. ^{[1
]}

机构：

[1] Clinical Eval. of Med./Therapeutics, Grad. Sch. of Pharmaceutical Sci., Osaka University, Suita, Osaka 565-0871

[2] Japan Clinical Laboratories Inc., Bioassay Division, Osaka

[3] Osaka Pharmacology Research Clinic, Osaka

来源：

The Pharmacogenomics Journal | 2004年 / 4卷 / 1期

关键词：

Clinical; CYP3A5; Nifedipine; Pharmacokinetics; Polymorphism;

D O I：

10.1038/sj.tpj.6500218

中图分类号：

学科分类号：

摘要：

CYP3A5 expression is regulated by single-nucleotide polymorphisms (SNPs). The CYP3A5 genotype might contribute to a marked interindividual variation in CYP3A-mediated metabolism of drugs. Nifedipine is a typical substrate of CYP3A4 and CYP3A5 in vitro. The aim of this study was to elucidate the influence of the CYP3A5 genotype on nifedipine disposition in healthy subjects. A single capsule containing 10 mg of nifedipine was administered to 16 healthy male Japanese subjects (eight subjects: CYP3A5*1/*3; eight subjects: CYP3AS5*/3*3). Blood samples were collected to analyze the pharmacokinetics of serum nifedipine and nitropyridine metabolite (M-I). The area under the plasma concentration-time curve (AUC), the peak plasma concentration (Cmax) and the terminal half-life (t1/2) of nifedipine, and the ratio of the nifedipine AUC to M-I AUC showed large intragroup variations, but no significant differences between the two genotypes. Based on the present findings, the functional relevance of CYP3A5 polymorphism should be re-evaluated in clinical trials. © 2004 Nature Publishing Group. All rights reserved.

引用

页码：34 / 39

页数：5

共 29 条

[1] Cholerton S., Daly A.K., Idle J.R., The role of individual human cytochromes P450 in drug metabolism and clinical response, Trends Pharmacol. Sci., 13, pp. 434-439, (1992)
[2] Shimada T., Yamazaki H., Mimura M., Inui Y., Guengerich F.P., Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians, J. Pharmacol. Exp. Ther., 270, pp. 414-423, (1994)
[3] Kuehl P., Zhang J., Lin Y., Lamba J., Assem M., Schuetz I., Et al., Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression, Nat. Genet., 27, pp. 383-391, (2001)
[4] Chou F.C., Tzeng S.J., Huang J.D., Genetic polymorphism of cytochrome P450 3A5 in Chinese, Drug Metab. Dispos., 29, pp. 1205-1209, (2001)
[5] Hustert E., Haberl M., Burk O., Wolbold R., He Y.Q., Klein K., Et al., The genetic determinants of the CYP3A5 polymorphism, Pharmacogenetics, 11, pp. 773-779, (2001)
[6] Fukuen S., Fukuda T., Maune H., Ikenaga Y., Yamamoto I., Inaba T., Et al., Novel detection assay by PCR-RFLP and frequency of the CYP3A5 SNPs, CYP3A5*3 and *6, in a Japanese population, Pharmacogenetics, 12, pp. 331-334, (2002)
[7] Aoyama T., Yamano S., Waxman D.J., Lapenson D.P., Meyer U.A., Fischer V., Et al., Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine, J. Biol. Chem., 264, pp. 10388-10395, (1989)
[8] Wrighton S.A., Brian W.R., Sari M.A., Iwasaki M., Guengerich P.P., Raucy J.L., Et al., Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3), Mol. Pharmacol., 38, pp. 207-213, (1990)
[9] Gillam E.M., Wunsch R.M., Ueng Y.F., Shimada T., Reilly P.E., Kamataki T., Et al., Expression of cytochrome P450 3A7 in Escherichia coli: Effects of 5′ modification and catalytic characterization of recombinant enzyme expressed in bicistronic format with NADPH-cytochrome P450 reductase, Arch. Biochem. Biophys., 346, pp. 81-90, (1997)
[10] Azuma J., Yamamoto I., Watase T., Seto Y., Tanaka T., Kato M., Et al., Effects of grapefruit juice on pharmacokinetics of the calcium antagonists nifedipine and nisoldipine, Jpn. Pharmacol. Ther. (Japanese), 24, pp. 267-276, (1996)

← 1 2 3 →