Abstract

1. Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.

2. The present study aimed to investigate the metabolic activation of ZOL in vitro and in vivo. ZOL-derived glutathione (GSH) and N-acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.

3. ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.

4. ZOL can be metabolized to an α,β-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.

摘要

1. 佐米曲坦（ZOL）是曲坦类的一员，已用于治疗偏头痛，疗效确切。然而，已经报道了几例与 ZOL 相关的肝损伤病例，其潜在机制仍不清楚。

2. 本研究旨在研究 ZOL在体外和体内的代谢活化。在大鼠肝微粒体孵育中检测到ZOL 衍生的谷胱甘肽 (GSH) 和N-乙酰半胱氨酸 (NAC) 缀合物。此外，分别在给予 ZOL 的大鼠的胆汁和尿液中也发现了 GSH 和 NAC 结合物。

3. 在 ZOL 处理的大鼠原代肝细胞中也观察到了 ZOL 衍生的 GSH 缀合物 M1，并且通过与奎尼丁（CYP2D6 的选择性抑制剂）预培养抑制了 M1 的形成。结合重组 P450 酶孵育，我们发现 CYP2D6 是负责 ZOL 代谢活化的主要酶。

4. ZOL 可通过 CYP2D6 代谢为α , β -不饱和亚胺中间体。用奎尼丁预处理原代肝细胞能够逆转 ZOL 诱导的细胞毒性。这一发现有助于理解 ZOL 相关肝脏不良反应所涉及的机制。