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CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro

The Pharmacogenomics Journal volume 1, pages 288–292 (2001)Cite this article

Abstract

Candesartan cilexetil is an angiotensin II receptor antagonist, and candesartan, its active metabolite, is metabolized by CYP2C9. However, the effect of CYP2C9*3 on candesartan metabolism is not established. We characterized the kinetics of candesartan by CYP2C9*1/*1 and CYP2C9*1/*3 in human liver microsomes. The difference between the two was not significant. Subsequently, CYP2C9*1 and CYP2C9*3 (Leu359) were expressed in yeast, and the kinetics of candesartan were determined. The wild-type showed the lower Km (345 vs 439 μM; 3/4) and higher Vmax/Km (1/3) than the Leu359 variant. Also, we investigated potential interaction between candesartan and warfarin with both the wild-type and the Leu359 variant. Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (Ki = 17 μM) greater than by the Leu359 variant (Ki = 36 μM). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1.

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References

  1. Shibouta Y, Inada Y, Ojima M, Wada T, Noda M, Sanada T et al. Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2′-(1H-ttrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11874), and its prodrug, (±)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116) J Pharm Exp Ther 1993 266: 114–120

    CAS  Google Scholar 

  2. McClellan KJ, Goa KL . Candesartan cilexetil Drugs 1998 56: 847–869

    Article  CAS  Google Scholar 

  3. Miners JO, Birkett DJ . Cytochrome P4502C9: an enzyme of major importance in human metabolism Br J Clin Pharmacol 1998 45: 525–538

    Article  CAS  Google Scholar 

  4. Wang Sl, Huang J, Lai MD, Tsai JJ . Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese Pharmacogenetics 1995 5: 37–42

    Article  CAS  Google Scholar 

  5. Nasu K, Kubota T, Ishizaki T . Genetic analysis of CYP2C9 polymorphism in a Japanese population Pharmacogenetics 1997 7: 405–449

    Article  CAS  Google Scholar 

  6. Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3 Pharmacogenetics 1997 7: 361–367

    Article  CAS  Google Scholar 

  7. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism Pharmacogenetics 1996 6: 341–349

    Article  CAS  Google Scholar 

  8. Odani A, Hashimoto Y, Otsuki Y, Uwai Y, Hattori H, Furusho K et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy Clin Pharmacol Ther 1997 62: 287–292

    Article  CAS  Google Scholar 

  9. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE . Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant form Arch Biochem Biophys 1996 333: 447–458

    Article  CAS  Google Scholar 

  10. John OM, Sally C, Donald JB, Joyce AG . Torsemide metabolism by CYP2C9 variants and other human CYP2C subfamily enzymes Pharmacogenetics 2000 10: 267–270

    Article  Google Scholar 

  11. Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT . Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele Pharmacogenetics 1999 9: 71–80

    Article  CAS  Google Scholar 

  12. Yamazaki H, Inoue K, Chiba K, Ozaa N, Kawai T, Suzuki Y et al. Comparative studies on the catalytic roles of cytohrome P450 2C9 and its Cys- and Leu-variants in the oxidation of warfarin, flurbiprofen, and diclofenac by human liver microsomes Biochem Pharmacol 1998 56: 243–253

    Article  CAS  Google Scholar 

  13. Bourrie M, Meunier V, Berger Y, Fabre G . Role of cytochrome P-4502C9 in irbesartan oxidation by human liver microsomes Drug Metab Dispos 1999 27: 288–296

    CAS  Google Scholar 

  14. Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD . Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor J Pharmacol Exp Ther 2000 293: 453–459

    CAS  Google Scholar 

  15. Hemeryck A, De Vriendt C, Belpaire FM . Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes Eur J Clin Pharmacol 1999 54: 947–951

    Article  CAS  Google Scholar 

  16. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K . CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates Pharmacogenetics 2000 10: 95–104

    Article  CAS  Google Scholar 

  17. Taavitssainen P, Kiukaanniemi K, Pelkonen O . In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists Eur J Clin Pharmacol 2000 56: 135–140

    Article  Google Scholar 

  18. Takahashi H, Kashima T, Nomoto S, Iwade K, Tainaka H, Shimizu T, et al. Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA–expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the the corresponding CYP2C9 genotypes Pharmacogenetics 1998 8: 365–373

    Article  CAS  Google Scholar 

  19. Sakaki T, Akiyoshi S . M, Yabusaki Y, Ohkawa H. Organella-targeted expression of rat liver cytochrome P450c27 in yeast J Biol Chem 1992 267: 16497–16502

    CAS  Google Scholar 

  20. Wan J, Imaoka S, Chow T, Hiroi T, Yabusaki Y, Funae Y . Expression of four rat CYP2D isoforms in Saccharomyces cerevisiae and their catalytic specificity Arch Biochem Biophys 1997 348: 383–390

    Article  CAS  Google Scholar 

  21. Murakami H, Yabusaki Y, Ohkawa H . Expression of rat NADPH-cytochrome P-450 reductase cDNA in Saccharomyces cerevisiae DNA 1986 5: 1–10

    Article  CAS  Google Scholar 

  22. Miyabayashi T, Okuda T, Motohashi M, Izawa K, Yashiki T . Quantitation of a new potent angiotensin II receptor antagonist, TCV-116, and its metabolites in human serum and urine J Chromatogr B 1996 677: 123–132

    Article  Google Scholar 

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Authors and Affiliations

  1. Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    T Hanatani, T Fukuda, M Ikeda & J Azuma

  2. The Organization for Pharmaceutical Safety and Research, Tokyo, Japan

    T Fukuda

  3. Department of Chemical Biology, Osaka City University Medical School, Osaka, Japan

    S Imaoka, T Hiroi & Y Funae

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  1. T Hanatani
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  2. T Fukuda
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  7. J Azuma
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Correspondence to J Azuma.

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Hanatani, T., Fukuda, T., Ikeda, M. et al. CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro. Pharmacogenomics J 1, 288–292 (2001). https://doi.org/10.1038/sj.tpj.6500063

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  • DOI: https://doi.org/10.1038/sj.tpj.6500063

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