Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide

Abstract

Objective: Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C8 on the pharmacokinetics and pharmacodynamics of the meglitinide analog antidiabetic drug repaglinide. Methods: We genotyped 28 healthy volunteers who had participated in our pharmacokinetic studies on repaglinide for variant alleles of the CYP2C8. Each subject ingested a 0.25-mg dose of repaglinide, and plasma drug and blood glucose concentrations were monitored for 7 hours after dosing. Results: There were 19 subjects (68%) with the CYP2C8*1/*1 genotype (wild type), 6 subjects (21%) with the CYP2C8*1/*3 genotype, and 3 subjects (11%) with the CYP2C8*1/*4 genotype. In the 3 genotypic groups, the mean ± SD area under the plasma repaglinide concentration-time curve from time 0 to infinity [AUC(0-∞)] was 5.8 ± 2.5 ng · h/mL for CYP2C8*1/*1, 3.6 ± 0.9 ng · h/mL for CYP2C8*1/*3, and 5.1 ± 3.6 ng · h/mL for CYP2C8*1/*4. The mean AUC(0-∞) of repaglinide was 45% (P < .005) lower and the peak concentration in plasma was 39% lower (P