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Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.


ABSTRACT: To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers.Prospective, open-label, single-dose pharmacokinetic study.University of Colorado Hospital Clinical and Translational Research Center.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).Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study.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).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.

SUBMITTER: Aquilante CL 

PROVIDER: S-EPMC3760990 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.

Aquilante Christina L CL   Wempe Michael F MF   Spencer Samantha H SH   Kosmiski Lisa A LA   Predhomme Julie A JA   Sidhom Maha S MS  

Pharmacotherapy 20130526 9


<h4>Study objectives</h4>To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers.<h4>Design</h4>Prospective, open-label, single-dose pharmacokinetic study.<h4>Setting</h4>University of Colorado Hospital Clinical and Translational Research Center.<h4>Participants</h4>Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 partici  ...[more]

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