Clinical poisoning events involving yunaconitine (YAC), a toxic Aconitum alkaloid, occur more and more frequently, and whether the mechanism is correlated with metabolism-based interactions remains unknown. This study aimed to reveal the presumable mechanism by clarifying the metabolic profiles and kinetic-based mechanism of YAC. YAC could be oxidized into 20 metabolites by human liver microsomes, while CYP3A4 have a critical metabolic superiority. Sixteen of the metabolites were primary generated by CYP3A4, and 4 of them were generated only by CYP3A4. The presence of CYP3A inhibitor ketoconazole (KCZ) significantly suppressed the generation of all the 20 metabolites, with 9 of them being suppressed completely (P < 0.05). The plasma exposure (C_max and AUC_0-t values), cardiotoxicity and neurotoxicity of YAC enhanced remarkably in mice when Cyp3a were inhibited (P < 0.05). Moreover, the CYP3A4-based kinetics of YAC is an example of substrate inhibition, and the inhibitory manner of YAC on CYP3A4 was competitive, with K_i value being 1.76 μmol/L. Overall, YAC was a sensitive substrate and moderately competitive inhibitor of CYP3A4. The inhibition on CYP3A4 could sharply increase the in vivo exposure and toxicity of YAC. Thus, clinical poisoning events involving YAC may be highly correlated with CYP3A4-mediated interactions.

涉及有毒乌头生物碱尤乌头碱（YAC）的临床中毒事件越来越频繁地发生，其机制是否与基于代谢的相互作用相关仍不清楚。本研究旨在通过阐明 YAC 的代谢特征和动力学机制来揭示可能的机制。YAC可以被人肝微粒体氧化成20种代谢物，而CYP3A4具有关键的代谢优势。其中 16 种代谢物主要由 CYP3A4 产生，其中 4 种代谢物仅由 CYP3A4 产生。CYP3A抑制剂酮康唑（KCZ）的存在显着抑制了所有20种代谢物的产生，其中9种代谢物被完全抑制（P  < 0.05）。抑制Cyp3a后，YAC对小鼠的血浆暴露量（C _max和AUC _{0-t值）、心脏毒性和神经毒性显着增强（} P  < 0.05）。此外，YAC基于CYP3A4的动力学是底物抑制的一个例子，YAC对CYP3A4的抑制方式是竞争性的，K _i值为1.76 μmol/L。总体而言，YAC 是 CYP3A4 的敏感底物和适度竞争性抑制剂。对CYP3A4的抑制会急剧增加YAC的体内暴露和毒性。因此，涉及 YAC 的临床中毒事件可能与 CYP3A4 介导的相互作用高度相关。