title: Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers.
abstract: 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 sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three 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. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml versus 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 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (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.
authors.affiliation: Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa, Madrid, Spain. teresa.cabaleiro@salud.madrid.org
authors.forename: Teresa
authors.initials: T
authors.lastname: Cabaleiro
authors.forename: Manuel
authors.initials: M
authors.lastname: Román
authors.forename: Dolores
authors.initials: D
authors.lastname: Ochoa
authors.forename: María
authors.initials: M
authors.lastname: Talegón
authors.forename: Rocío
authors.initials: R
authors.lastname: Prieto-Pérez
authors.forename: Aneta
authors.initials: A
authors.lastname: Wojnicz
authors.forename: Rosario
authors.initials: R
authors.lastname: López-Rodríguez
authors.forename: Jesús
authors.initials: J
authors.lastname: Novalbos
authors.forename: Francisco
authors.initials: F
authors.lastname: Abad-Santos
mesh_terms: D000483:Alleles; D057911:Angiotensin Receptor Antagonists / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D012016:Reference Values; D012737:Sex Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8