Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype

Abstract

Objectives: Rosiglitazone is metabolically inactivated predominantly via the cytochrome P450 (CYP) enzyme CYP2C8. The functional impact of the CYP2C8*3 allele coding for the Arg139Lys and Lys399Arg amino acid substitutions is controversial. The purpose of this was to clarify the role of this polymorphism with regard to the pharmacokinetics and clinical effects of rosiglitazone. Methods: From a large sample of healthy volunteers, 14 carriers of the CYP2C8*1/*1 allele, 13 carriers of the *1/*3 allele, and 4 carriers the *3/*3 allele were selected for a clinical study. Rosiglitazone (8 mg) single-dose and multiple-dose pharmacokinetics and its effects on glucose level and body weight were monitored. Plasma and urine concentrations of rosiglitazone and desmethylrosiglitazone were measured, and kinetics was analyzed by noncompartmental and population-kinetic compartmental methods. Results: Mean total clearance values were 0.033 L · h-1 · kg-1 (95% confidence interval [CI], 0.030-0.037 L · h-1 · kg-1), 0.038 L · h-1 · kg-1 (95% CI, 0.033-0.044 L · h-1 · kg-1), and 0.046 L · h-1 · kg-1 (95% CI, 0.033-0.058 L · h-1 · kg-1) in carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, on day 1 (P = .02, ANOVA [F test]). Rosiglitazone kinetics could be adequately described by a 1-compartmental model with first-order absorption. Besides CYP2C8 genotype, body weight was a significant covariate (P