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 coadministered. BIC showed time-, concentration-, and NADPH-dependent inhibitory effects on CYP2C19. BIC (2.0 μM) inhibited CYP2C19 activity by approximately 64% after 9 minutes of incubation at 30 °C, and KI and kinact 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 did not show protective effects against BIC-induced enzyme inactivation. It is speculated that carbene intermediates were involved in BIC-induced inactivation of CYP2C19 because K3Fe (CN)6 restored the enzymatic activity. In addition, BIC and CDR extract pretreatment resulted in a significant decrease in the Cmax and area under the curve of the plasma thiol metabolite in rats given clopidogrel. SIGNIFICANCE STATEMENT: This study identifies bicuculline, a major component of Corydalis Decumbentis Rhizoma, as a mechanism-based inhibitor of CYP2C19 through carbene-mediated coordination with heme iron. Such inhibition reduces clopidogrel activation and indicates clinically relevant herb-drug interactions.