title: Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid.
abstract: OBJECTIVE
  The effects of various polymorphisms in cytochrome P450 (CYP) enzyme and transporter genes on the pharmacokinetics (PK) of simvastatin were evaluated in healthy Korean men.
  
  
  METHODS
  Plasma concentration data for simvastatin and simvastatin acid were pooled from four phase I studies comprising 133 participants. The polymorphisms CYP2D6*4, CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, CYP2C19*2, CYP2C19*3, CYP2A6*7, and CYP2A6*9; SLCO1B1 rs4149056, rs2306283, and rs4149015; ABCB1 rs1128503, rs2032582, and rs1045642; and ABCG2 rs2231142 were evaluated in each participant. Noncompartmental PK results were compared by genotype.
  
  
  RESULTS
  CYP2D6*5 and CYP2D6*14 were found to be associated with a higher area under the curve (AUC) for simvastatin, whereas the AUC of simvastatin acid was significantly increased in patients with the SLCO1B1 rs4149056, ABCG2 rs2231142, and CYP2D6*41 allele variants. Patients with the CYP2D6*41 variant showed a higher peak serum concentration (Cmax) of both simvastatin and simvastatin acid. The SLCO1B1 rs4149056 and rs4149015 polymorphisms were associated with an increased AUC ratio (i.e. ratio of simvastatin acid to simvastatin), whereas the SLCO1B1 rs4149056 and CYP2D6*5 variants were related to a higher Cmax ratio.
  
  
  CONCLUSIONS
  The CYP2D6*5, CYP2D6*14, CYP2D6*41, CYP3A5*3, SLCO1B1 rs4149056 and rs4149015, and ABCG2 rs2231142 genetic polymorphisms are associated with the PK of both simvastatin and simvastatin acid. This could potentially be used as a basis for individualized simvastatin therapy by predicting the clinical outcomes of this treatment.
authors.affiliation: aDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine bDaewoong Pharmaceutical Company, Seoul cDepartment of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon dDepartment of Clinical Pharmacology, Busan Paik Hospital eClinical Trials Center, Pusan National University, Busan, Korea.
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Choi
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Cho
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.forename: Sangmin
authors.initials: S
authors.lastname: Choe
authors.forename: Jin Ah
authors.initials: JA
authors.lastname: Jung
authors.forename: Seok-Joon
authors.initials: SJ
authors.lastname: Jin
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019821:Simvastatin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C063287:simvastatin acid; D019821:Simvastatin; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A