Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, Japan.
Drug Metab Pharmacokinet. 2020 Apr;35(2):238-243. doi: 10.1016/j.dmpk.2020.01.006. Epub 2020 Feb 28.
Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.
奈韦拉平（NVP）广泛用作 HIV-1 的非核苷类逆转录酶抑制剂，但它与严重的皮肤和肝脏损伤有关。这些不良反应的机制尚不清楚，但 NVP 的代谢激活被认为与损伤过程有关。到目前为止，已经报道了几种 NVP 的代谢激活途径。在这项研究中，为了确定主要导致 CYP 抑制和肝损伤的 NVP 反应性代谢物，我们合成了五个设计用于避免提议的生物活化途径的 NVP 类似物，并评估了它们的代谢稳定性、CYP3A4 时间依赖性抑制活性和细胞毒性。结果表明，只有 NVP 的嘧啶类似物可以避免形成反应性环氧化物中间体，不会抑制 CYP3A4。在该化合物之外，其他可避免生成反应性醌-亚甲基中间体的合成化合物对 CYP3A4 的抑制作用与 NVP 相当或更强。NVP 的嘧啶类似物在表达主要四种 CYP 酶和 CYP 氧化还原酶的 HepG2 和转染 HepG2 细胞中没有诱导细胞毒性。这些结果表明 NVP 的环氧化物中间体能在 NVP 诱导的肝损伤中起重要作用。
