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 6 75.8 ng/ml versus 282.1 6 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 6 0.4 hours) than in volunteers with the wild-type genotype (2.3 6 0.1 hours) (P £ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 6 0.57 l/h·kg) than those with the wild-type genotype (0.48 6 0.72 l/h·kg; P £ 0.01) and carriers of the *3 allele (0.35 6 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.

Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

“…The SNP frequencies observed in the study group are consistent with those previously described in healthy Spaniards subjects [20,[25][26][27][28][29] and are at…”

Differences inCYP2C9Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex

“…Thus in the present study women on OC use were excluded. Similar to our finding, no significant effect of sex on CYP2C9 enzyme activity and losartan pharmacokinetics is reported (Cabaleiro et al, 2013;Sica et al, 2005). A recent study highlighted the role of sex for the activity of CYP2C9, but the authors described the lack of information about the females' consumption of oral contraceptives as limitation of their findings (Llerena et al, 2014).…”

Evaluation of Adherence Should Become an Integral Part of Assessment of Patients With Apparently Treatment-Resistant Hypertension

“…[76][77][78] Some angiotensin type I receptors blockers (losartan, irbesartan, candesartan) are metabolized by the polymorphic CYP2C9. 79 Finally, calcium antagonists are mainly substrates for highly polymorphic CYP3A4 3A5 enzymes. [80][81][82] Table 3 summarizes the pharmacokinetic characteristics of the most frequently used antihypertensive drugs belonging to the 5 main classes.…”