Influence of CYP2C8☆2 on the Pharmacokinetics of Pioglitazone in Healthy African-American Volunteers

STUDY OBJECTIVES To determine the influence of the Cytochrome P450 (CYP) 2C8(star)2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. DESIGN Prospective, open-label, single-dose pharmacokinetic study. SETTING University of Colorado Hospital Clinical and Translational Research Center. PARTICIPANTS Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8(star)1/(star)1 (9 participants), CYP2C8(star)1/(star)2 (7 participants), and CYP2C8(star)2/(star)2 (1 participant). INTERVENTION Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. MEASUREMENTS AND MAIN RESULTS Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8(star)1/(star)1 genotype and CYP2C8(star)2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)(0-infinity) and half-life (t(1/2)) did not differ significantly between CYP2C8(star)1/(star)1 and CYP2C8(star)2 carriers (AUC(0-infinity) 7331 +/- 2846 vs 10431 +/- 5090 ng*h/ml, p=0.15, t(1/2) 7.4 +/- 2.7 vs 10.5 +/- 4.0 h, p=0.07). M-III and M-IV AUC(0-48) also did not differ significantly between genotype groups. However, the M-III: pioglitazone AUC(0-48) ratio was significantly lower in CYP2C8(star)2 carriers than CYP2C8(star)1 homozygotes (0.70 +/- 0.15 vs 1.2 +/- 0.37, p=0.006). Similarly, CYP2C8(star)2 carriers had a significantly lower M-III: M-IV AUC(0-48) ratio than participants with the CYP2C8(star)1/(star)1 genotype (0.82 +/- 0.26 vs 1.22 +/- 0.26, p=0.006). CONCLUSION These data suggest that CYP2C8(star)2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC(0-48) ratio of M-III: parent drug, and the AUC(0-48) ratio of M-III: M-IV. Larger studies are needed to further investigate the impact of CYP2C8(star)2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.