CYP2C9*3 influences the metabolism and the drug-interaction of candesartan in vitro.
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.
Hanatani
T
T
Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Fukuda
T
T
Ikeda
M
M
Imaoka
S
S
Hiroi
T
T
Funae
Y
Y
Azuma
J
J
D000483:Alleles; D000925:Anticoagulants / Q000378:metabolism / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D001562:Benzimidazoles / Q000378:metabolism*; D001713:Biphenyl Compounds; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007930:Leucine / Q000235:genetics; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism / Q000493:pharmacokinetics
D000925:Anticoagulants; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011994:Recombinant Proteins; D013777:Tetrazoles; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D007930:Leucine; C081643:candesartan