CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects

Background: Although cytochrome P450 (CY-P) 2C9 was thought to be the main pathway for glyburide (INN, glibenclamide) metabolism in vivo, studies in vitro indicated that CYP2C19 had a more dominant effect. This study investigated the relative influence of CYP2C9 and CYP2C19 genotypes on the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects. Methods: Three groups of healthy male Chinese subjects (n = 6 per group) were enrolled, as follows: group 1, CYP2C9*1/*1 and CYP2CI9 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2CI9 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. Subjects received single oral doses of 5 mg glyburide. Multiple blood samples were collected, and the plasma glyburide concentrations were determined by an HPLC method. The plasma glucose and insulin concentrations were also measured up to 2 hours after dosing. Results: No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the C gamma P2C9*1/*1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) and elimination half-life (t1/2) were 0.46 +/- 0.13 mu g center dot h/mL versus 0.57 +/- 0.11 mu g center dot h/mL (P =.569) and 2.09 +/- 0.22 hours versus 2.24 +/- 0.27 hours (P =.72). However, significant increases in AUC(0-infinity), (125% and 82%; P =.008 and .024, respectively) and t1/2 (71% and 60%; P =.003 and .007, respectively) were observed when C gamma P2C9*1/*3 subjects (group III) were compared with C gamma P2C9*1/*1 subjects in group I or II. Blood glucose reductions at 2 hours after dosing were 41.8%, 23.9%, and 27.7% in groups I, II, and III, respectively (P =.029), and hypoglycemia developed in 3 of 6 C gamma P2C9*1/*3 carriers and 2 of 12 C gamma P2C9*1/*1 carriers. Conclusion: CYP2C9, but not CYP2CI9, polymorphism appears to exert a dominant influence on glyburide pharmacokinetics; and pharmacodynamics in vivo. Further studies in diabetic patients with long-term dosing are warranted to confirm these findings.