Abstract
Background Recent in vitro studies showed that both CYP2C9 and 2C19 contributed to the metabolism of glibenclamide (glyburide). This study investigates the relative in vivo contribution of CYP2C9 and 2C19 to glibenclamide pharmacokinetics. Methods Eighteen healthy male Chinese subjects were divided into 3 groups: CYP2C19 EM/CYP2C9*1/*1 (group 1, n=6), CYP2C19 PM/CYP2C9*1/*1 (group 2, n=6), and CYP2C19 EM/CYP2C9*1/*3 (group 3, n=6). Subject received a single oral dose of 5 mg glibenclamide, and multiple blood samples were collected over 12h. Results No significant differences in glibenclamide pharmacokinetics were observed between CYP2C19 EM and PM subjects (group 1 vs 2). However, the plasma glibenclamide concentration was significantly higher in CYP2C9*1/*3 than CYP2C9*1/*1 subjects regardless of CYP2C19 genotype (group 3 vs 1 or 2), and their respective AUC0-∞ were 1.03±0.50, 0.46±0.13 and 0.57±0.11 μg•h/ml (ANOVA, p<0.05), and respective t1/2 were 3.58± 1.25, 2.09± 0.22 and 2.24± 0.27h (ANOVA p<0.05). In addition, 50% of CYP2C9*1/*3 subjects and 17% of CYP2C9*1/*1 subjects developed blood glucose levels below 3 mmol/L and required oral glucose administration. Conclusion CYP2C9 but not 2C19 polymorphism appears to exert dominant influence on glibenclamide metabolism. In CYP2C9*1/*3 heterozygote subjects, the pharmacokinetics and pharmacodynamics of glibenclamide were markedly changed, and the glibenclamide dosage may need to be adjusted to reduce the risk of hypoglycemia. Clinical Pharmacology & Therapeutics (2005) 77, P23–P23; doi: 10.1016/j.clpt.2004.11.087
Published Version
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