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Evaluation of the relationship between gender, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers.

Drug Metab Dispos. 2012 Nov 1;

Authors: Cabaleiro T, Roman M, Ochoa D, Talegon M, Prieto-Perez R, Wojnicz A, Lopez-Rodriguez R, Novalbos J, Abad-Santos F


AIMS - Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between gender, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. METHODS - The study population comprised 246 healthy volunteers from 7 single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from 3 valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. RESULTS - Gender only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml vs. 282.1 ± 30.8 ng/ml, p≤0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 h) than in volunteers with the wild-type genotype (2.3 ± 0.1 h) (p≤0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg, p≤0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg, p≤0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

PMID: 23118328 [PubMed - as supplied by publisher]