title: Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone.
abstract: OBJECTIVE
  The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate).
  
  
  METHODS
  In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period.
  
  
  RESULTS
  Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P = 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02).
  
  
  CONCLUSIONS
  CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO 80045, USA. christina.aquilante@ucdenver.edu
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kosmiski
authors.forename: David W A
authors.initials: DW
authors.lastname: Bourne
authors.forename: Lane R
authors.initials: LR
authors.lastname: Bushman
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Daily
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Hammond
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hopley
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Kanack
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
authors.forename: Merry
authors.initials: M
authors.lastname: Le
authors.forename: Julie A
authors.initials: JA
authors.lastname: Predhomme
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rower
authors.forename: Maha S
authors.initials: MS
authors.lastname: Sidhom
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D011110:Polymorphism, Genetic; D045162:Thiazolidinediones / Q000493:pharmacokinetics*
chemical_list: D000960:Hypolipidemic Agents; D045162:Thiazolidinediones; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil; D000077205:Pioglitazone