title: CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control.
abstract: BACKGROUND
  Statins are indicated for prevention of atherosclerotic cardiovascular disease. Metabolism of certain statins involves the cytochrome P450 3A (CYP3A) enzymes, and CYP3A4*22 significantly influences the dose needed for achieving optimal lipid control for atorvastatin, simvastatin, and lovastatin. CYP3A4/5 combined genotype approaches have proved useful in some studies involving CYP3A substrates. We intend to compare a combined genotype analysis to our previously reported single gene CYP3A4 analysis.
  
  
  METHODS
  A total of 235 patients receiving stable statin doses were genotyped and grouped by CYP3A4/5 status.
  
  
  RESULTS
  The number and demographic composition of the patients categorized into the combined genotype groups were consistent with those reported for other cohorts. Dose requirement was significantly associated with the ordered combined-genotype grouping; median daily doses were nearly 40% greater for CYP3A4/5 intermediate metabolizers compared with poor metabolizers, and median daily doses were nearly double for extensive metabolizers compared with poor metabolizers. The combined-genotype approach, however, did not improve the genotype-dosage correlation p-values when compared with the previously-reported analysis; values changed from 0.129 to 0.166, 0.036 to 0.185, and 0.014 to 0.044 for atorvastatin, simvastatin, and the combined statin analysis, respectively.
  
  
  CONCLUSIONS
  The previously-reported single-gene approach was superior for predicting statin dose requirement in this cohort.
authors: Department of Pharmacology, The Ohio State University, Columbus, OH, USA. Joseph.kitzmiller@osumc.edu
authors: Joseph Paul
authors: JP
authors: Kitzmiller
authors: Danielle M
authors: DM
authors: Sullivan
authors: Mitchell A
authors: MA
authors: Phelps
authors: Danxin
authors: D
authors: Wang
authors: Wolfgang
authors: W
authors: Sadee
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D008148:Lovastatin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D019821:Simvastatin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human