CYP3A 介导的托特罗定的体外和体内代谢激活,Chemical Research in Toxicology

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CYP3A 介导的托特罗定的体外和体内代谢激活
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2023-02-16 , DOI: 10.1021/acs.chemrestox.2c00389
Aixuan Wang ₁ , Qiang Zhao ₁ , Minglu Liu ₁ , Yang Wang ₁ , Guode Zhao ₁ , Weiwei Li ₂ , Ying Peng ₁ , Jiang Zheng _{1,

2}

Affiliation

托特罗定 (TOL) 是一种抗毒蕈碱药物，用于治疗出现尿频、尿急和急迫性尿失禁的膀胱过度活动症患者。TOL在临床使用过程中，发生了肝损伤等不良事件。本研究旨在调查可能与其肝毒性相关的 TOL 的代谢激活。在补充有 TOL、GSH/NAC/半胱氨酸和 NADPH 的小鼠和人肝微粒体孵育中发现了一种 GSH 结合物、两种 NAC 结合物和两种半胱氨酸结合物。检测到的偶联物表明产生了醌甲基化物中间体。在小鼠原代肝细胞和接受 TOL 的大鼠胆汁中也观察到相同的 GSH 结合物。在给予 TOL 的大鼠中观察到其中一种尿液 NAC 结合物。一种半胱氨酸偶联物是在含有来自施用 TOL 的动物的肝蛋白的消化混合物中发现的。观察到的蛋白质修饰是剂量依赖性的。CYP3A 主要催化 TOL 的代谢活化。酮康唑 (KTC) 预处理减少了 TOL 处理后小鼠肝脏和培养的原代肝细胞中 GSH 结合物的生成。此外，KTC 降低了原代肝细胞对 TOL 细胞毒性的敏感性。醌甲基化物代谢物可能参与 TOL 诱导的肝毒性和细胞毒性。酮康唑 (KTC) 预处理减少了 TOL 处理后小鼠肝脏和培养的原代肝细胞中 GSH 结合物的生成。此外，KTC 降低了原代肝细胞对 TOL 细胞毒性的敏感性。醌甲基化物代谢物可能参与 TOL 诱导的肝毒性和细胞毒性。酮康唑 (KTC) 预处理减少了 TOL 处理后小鼠肝脏和培养的原代肝细胞中 GSH 结合物的生成。此外，KTC 降低了原代肝细胞对 TOL 细胞毒性的敏感性。醌甲基化物代谢物可能参与 TOL 诱导的肝毒性和细胞毒性。

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In Vitro and In Vivo Metabolic Activation of Tolterodine Mediated by CYP3A

Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.

更新日期：2023-02-16

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