CYP3A4z.ast22 and CYP3A5z.ast3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort

Objective Simvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a combined CYP3A4/5 genotype-defined classification. Participants and methods Genotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotype-defined classification system. Results In Whites, CYP3A4*22 carriers (n = 42) had 14% higher SVA (P = 0.04) and 20% higher SV (P = 0.06) compared with noncarriers (n = 513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n = 8) had 170% higher SV (P < 0.01) than noncarriers (n = 267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n = 28) had 33% higher SV (P = 0.02) than CYP3A5 expressors (n = 247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA. Conclusion Genetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in self-reported African-Americans.