Mechanism-based inactivation of CYP2C19 by bicuculline and related alteration in pharmacokinetics of clopidogrel

Corydalis Decumbentis Rhizoma (CDR) is a traditional Chinese herbal medicine, which has been clinically used for treating migraine, relieving the symptoms of rheumatoid arthritis, and reversing osteoporosis. Bicuculline (BIC) is one of the main bioactive ingredients present in CDR. The purpose of this study was to comprehensively investigate the interaction of BIC with cytochrome P450 enzymes and the alteration of the pharmacokinetic properties of the active thiol metabolite 4 of clopidogrel when co-administered. BIC showed time-, concentration-, and NADPH-dependent inhibitory effects on CYP2C19. BIC (2.0 μM) inhibited CYP2C19 activity by about 64% after 9 min of incubation at 30 °C, and K I and k inact were 0.09 μM and 0.051 min -1 , respectively. Ticlopidine showed a significant protective effect against BIC-induced CYP2C19 inactivation. Dialysis did not restore the inhibited enzyme activity induced by BIC. Moreover, the addition of catalase/superoxide dismutase or glutathione (GSH) did not show protective effects against BIC-induced enzyme inactivation. It is speculated that carbene intermediates were involved in BIC-induced inactivation of CYP2C19, since K 3 Fe (CN) 6 restored the enzymatic activity. In addition, BIC and CDR extract pretreatment resulted in a significant decrease in the C max and AUC of the plasma thiol metabolite in rats given clopidogrel.