Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers.
Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography-tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose.
Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC(0-∞) and C(max) in group C were significantly higher [83.94 ± 40.41 vs. 16.39 ± 5.10 μg·h/mL (P = 0.000) and 1.50 ± 0.85 vs. 0.45 ± 0.18 μg/mL (P = 0.000)], and the oral clearance was significantly lower [1.17 ± 0.63 vs. 5.38 ± 1.86 L/h (P = 0.000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33.47 ± 12.39 vs. 19.34 ± 10.45 h), but the difference was not significant (P = 0.052). The increase in serum glucose level at 11 h after dosing (ΔC(glu11)) in group C was significantly higher than that of group A (-1.08 ± 0.42 vs. 0.22 ± 1.01 mmol/L, P = 0.022). The corresponding insulin levels showed no difference between the two groups.
Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.