title: CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: aCenter for Pharmacogenomics, College of Medicine, The Ohio State University,Columbus, Ohio bChildren's Hospital Oakland Research Institute, Oakland, California, USA cDipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy.
authors: Joseph P
authors: JP
authors: Kitzmiller
authors: Jasmine A
authors: JA
authors: Luzum
authors: Damiano
authors: D
authors: Baldassarre
authors: Ronald M
authors: RM
authors: Krauss
authors: Marisa W
authors: MW
authors: Medina
mesh_terms: D001741:Black or African American / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D003460:Crystallization; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D057566:Self Report; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood*; D014481:United States; D044465:White People / Q000235:genetics*
chemical_list: D002784:Cholesterol; D019821:Simvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human