Bulleyaconitine A is a sensitive substrate and competitive inhibitor of CYP3A4: One of the possible explanations for clinical adverse reactions
Bulleyaconitine A is a sensitive substrate and competitive inhibitor of CYP3A4: One of the possible explanations for clinical adverse reactions
复制标题
Bulleyaconitine A 是 CYP3A4 的敏感底物和竞争性抑制剂：临床不良反应的可能解释之一
DOI：
10.1016/j.taap.2022.116024
复制
发表时间：
2022
影响因子：
3.8
通讯作者：
Lijun Zhu
中科院分区：
文献类型：
--
作者：
Xiaocui Li;Xiaowen Ou;Jiadong Ni;Yinghong Xu;Huilin Zuo;Yu Fu;Caihua Yang;Zhongxiang Zhao;Na Li;Hua Zhou;Rong Zhang;Zhongqiu Liu;Ling Fu;Lijun Zhu
Bulleyaconitine A（BLA）是一种有毒的乌头属生物碱，是一种强效镇痛药，临床上用于治疗类风湿性关节炎、骨关节炎和腰骶疼痛。BLA相关的不良反应频繁发生，但其潜在机制是否与药物代谢酶的代谢相互作用有关仍不清楚。本研究旨在阐明BLA的代谢特征及其与药物代谢酶的亲和作用和机制，以揭示BLA相关的不良反应是否受酶的调节。在与人肝微粒体和重组人细胞色素P450酶孵育后，我们发现BLA主要由CYP 3A代谢，其中CYP 3A 4几乎占绝对优势。在体外，CYP 3A 4抑制剂酮康唑显著抑制BLA的代谢。在体内，Cyp 3a抑制小鼠的AUC 0-∞值、心脏毒性和神经毒性均明显高于正常小鼠（P < 0.05）。在酶动力学研究中发现，BLA是CYP 3A 4的敏感底物，其特性与底物抑制一致（Km = 39.36 ± 10.47 μmol/L，Ks = 83.42 ± 19.65 μmol/L）。BLA对CYP 3A 4具有竞争性抑制作用，Ki = 53.64 μmol/L，与BLA共同孵育时，选择性底物咪达唑仑的固有清除率（克林特）显著降低（P < 0.05）。总体而言，BLA是CYP 3A 4的敏感底物和竞争性抑制剂，BLA的临床不良反应可能与CYP 3A 4介导的药物相互作用有关。
Bulleyaconitine A (BLA), a toxic Aconitum alkaloid, is a potent analgesic that is clinically applied to treat rheumatoid arthritis, osteoarthritis and lumbosacral pain. BLA-related adverse reactions occur frequently, but whether the underlying mechanism is related to its metabolic interplay with drug-metabolizing enzymes remains unclear. This study aimed to elucidate the metabolic characteristics of BLA and its affinity action and mechanism to drug-metabolizing enzymes to reveal whether BLA-related adverse reactions are modulated by enzymes. After incubation with human liver microsomes and recombinant human cytochrome P450 enzymes, we found that BLA was predominantly metabolized by CYP3A, in which CYP3A4 had an almost absolute advantage. In vitro, the CYP3A4 inhibitor ketoconazole noticeably suppressed the metabolism of BLA. In vivo, the AUC0-∞ values, cardiotoxicity and neurotoxicity of BLA in Cyp3a-inhibited mice were all obviously enhanced (P < 0.05) compared to those in normal mice. In the enzyme kinetics study, BLA was found to be a sensitive substrate of CYP3A4, and its characteristics were consistent with substrate inhibition (Km = 39.36 ± 10.47 μmol/L, Ks = 83.42 ± 19.65 μmol/L). BLA was further identified to be a competitive inhibitor of CYP3A4 with Ki = 53.64 μmol/L, since the intrinsic clearance (CLint) of midazolam, a selective CYP3A4 substrate, decreased significantly (P < 0.05) when incubated with BLA together in mouse liver microsomes. Overall, BLA is a sensitive substrate and competitive inhibitor of CYP3A4, and clinical adverse reactions of BLA may mechanistically related to the CYP3A4-mediated drug-drug interactions.