MechanisticInsights into CYP2A6 Inactivation by Visnaginand Its Impact on Pharmacokinetic Properties of Tegafur

Visnagin (VNG), a furanochromone, is a major active component of the plant Ammi visnaga (L.) Lam often used for the preparation of tea products. This study aims to comprehensively investigate the mechanism of VNG-mediated CYP2A6 enzyme inactivation and the effects of VNG on the pharmacokinetics of the antitumor drug tegafur. The results demonstrate that VNG irreversibly inhibits CYP2A6 in a time-, concentration-, and NADPH-dependent manner. This time-dependent inhibition was attenuated by coincubation with letrozole, a competitive inhibitor of CYP2A6. Glutathione and hydrogen peroxide/superoxide dismutase failed to reverse the VNG-induced inactivation of CYP2A6. GSH trapping experiments provided strong evidence for the formation of epoxide and/or γ-ketoaldehyde intermediates resulting from the metabolic activation of VNG. Furthermore, pretreatment with VNG extract significantly increased the plasma <i>C</i>_max and area under the curve of tegafur in rats.