Influence of CYP2C82 on the Pharmacokinetics of Pioglitazone in Healthy African-American Volunteers

Study Objectives To determine the influence of the Cytochrome P450 (CYP) 2C8*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*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*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*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). Conclusion 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.