Abstract

1. Lamotrigine is a phenyltriazine anticonvulsant used to treat epilepsy and bipolar disorder, with species-dependent metabolic profiles. In this study, we investigated the metabolism of lamotrigine in chimeric NOG-TKm30 mice transplanted with human hepatocytes (humanised-liver mice).

2. Substantial lamotrigine N2-glucuronidation activities were observed in the liver microsomes from humanised-liver mice, humans, marmosets, and rabbits, compared to those from monkeys, minipigs, guinea pigs, rats, and mice. Lamotrigine N2-glucuronidation activities in the liver microsomes from humanised-liver mice were dose-dependently inhibited by hecogenin, a specific inhibitor of the human UGT1A4.

3. The major metabolite in the hepatocytes from humanised-liver mice and humans was lamotrigine N2-glucuronide, whereas that in mouse hepatocytes was lamotrigine N2-oxide.

4. After a single oral dose of lamotrigine (10 mg/kg), the plasma levels of N2-glucuronide, N5-glucuronide, and N2-methyl were higher in humanised-liver mice compared to that in NOG-TKm30 mice. Lamotrigine N2-glucuronide was the most abundant metabolite in the urine in humanised-liver mice, similar to that reported in humans; whereas, lamotrigine N2-oxide was predominantly excreted in the urine in NOG-TKm30 mouse.

5. These results suggest that humanised-liver mice may be a suitable animal model for studying the UGT1A4 mediated-lamotrigine metabolism.

摘要

1. 拉莫三嗪是一种苯基三嗪抗惊厥药，用于治疗癫痫和双相情感障碍，具有物种依赖性代谢特征。在这项研究中，我们研究了拉莫三嗪在移植了人肝细胞的嵌合 NOG-TKm30 小鼠（人源化肝小鼠）中的代谢。

2. 与来自猴子、小型猪、豚鼠、大鼠和小鼠的肝微粒体相比，在人源化肝小鼠、人类、狨猴和兔子的肝微粒体中观察到了大量的拉莫三嗪 N2-葡萄糖醛酸化活性。人源化肝小鼠肝微粒体中的拉莫三嗪 N2-葡萄糖醛酸化活性被人 UGT1A4 的特异性抑制剂 hecogenin 剂量依赖性抑制。

3. 人源化肝小鼠和人类肝细胞中的主要代谢物是拉莫三嗪 N2-葡萄糖醛酸苷，而小鼠肝细胞中的主要代谢物是拉莫三嗪 N2-氧化物。

4. 单次口服拉莫三嗪 (10 mg/kg) 后，与 NOG-TKm30 小鼠相比，人源化肝小鼠的血浆 N2-葡糖苷酸、N5-葡糖苷酸和 N2-甲基水平更高。拉莫三嗪 N2-葡萄糖醛酸是人源化肝小鼠尿液中含量最高的代谢物，与人类报道的相似；而拉莫三嗪 N2-氧化物主要从 NOG-TKm30 小鼠的尿液中排泄。

5. 这些结果表明，人源化肝小鼠可能是研究 UGT1A4 介导的拉莫三嗪代谢的合适动物模型。