title: Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.
abstract: OBJECTIVE
  To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers.
  
  
  METHODS
  Prospective, open-label, single-dose pharmacokinetic study.
  
  
  METHODS
  University of Colorado Hospital Clinical and Translational Research Center.
  
  
  METHODS
  Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant).
  
  
  METHODS
  Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study.
  
  
  RESULTS
  Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331 ± 2846 vs 10431 ± 5090 ng*h/ml, p=0.15, t1/2 7.4 ± 2.7 vs 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 vs 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ± 0.26 vs 1.22 ± 0.26, p=0.006).
  
  
  CONCLUSIONS
  These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Samantha H
authors.initials: SH
authors.lastname: Spencer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kosmiski
authors.forename: Julie A
authors.initials: JA
authors.lastname: Predhomme
authors.forename: Maha S
authors.initials: MS
authors.lastname: Sidhom
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D011110:Polymorphism, Genetic / Q000235:genetics; D045162:Thiazolidinediones / Q000493:pharmacokinetics*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000077205:Pioglitazone
keywords: African-American; CYP2C8; pharmacogenetics; pharmacokinetics; pioglitazone; polymorphism