Objective: Simvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4z.ast22 and the loss-of-function CYP3A5z.ast3, has recently been reported. We aim to determine whether CYP3A4z.ast22 and CYP3A5z.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 CYP3A4z.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 CYP3A4z.ast22 and CYP3A5z.ast3 alleles were tested separately and in a combined CYP3A4/5 genotypedefined classification system.
Results: In Whites, CYP3A4z.ast22 carriers (n=42) had 14% higher SVA (P =0.04) and 20% higher SV (P=0.06) compared with noncarriers (n= 513). CYP3A5z.ast3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4z.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.
ASJC Scopus subject areas
- Molecular Biology
- Molecular Medicine