CYP3A4^z.ast22 and CYP3A5^z.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^z.ast22 and the loss-of-function CYP3A5^z.ast3, has recently been reported. We aim to determine whether CYP3A4^z.ast22 and CYP3A5^z.ast3 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^z.ast22, 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^z.ast22 and CYP3A5^z.ast3 alleles were tested separately and in a combined CYP3A4/5 genotypedefined classification system.

Results: In Whites, CYP3A4^z.ast22 carriers (n=42) had 14% higher SVA (P =0.04) and 20% higher SV (P=0.06) compared with noncarriers (n= 513). CYP3A5^z.ast3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4^z.ast22 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.