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 microM; 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 (K = 17microM) greater than by the Leu359 variant (Ki = 36 microM). These findings suggest that CYP2C9*3 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Anticoagulants / metabolism
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Anticoagulants / pharmacokinetics
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Antihypertensive Agents / metabolism
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Aryl Hydrocarbon Hydroxylases*
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Benzimidazoles / metabolism*
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Biphenyl Compounds
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Dose-Response Relationship, Drug
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Drug Interactions / physiology
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Humans
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Leucine / genetics
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Microsomes, Liver / enzymology
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Microsomes, Liver / metabolism
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / genetics
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Steroid 16-alpha-Hydroxylase*
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Steroid Hydroxylases / genetics
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Steroid Hydroxylases / metabolism*
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Tetrazoles / metabolism*
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Warfarin / metabolism
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Warfarin / pharmacokinetics
Substances
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Anticoagulants
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Antihypertensive Agents
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Benzimidazoles
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Biphenyl Compounds
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Recombinant Proteins
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Tetrazoles
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Warfarin
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Cytochrome P-450 Enzyme System
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Steroid Hydroxylases
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Steroid 16-alpha-Hydroxylase
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Leucine
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candesartan