期刊
XENOBIOTICA
卷 51, 期 10, 页码 1146-1154出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/00498254.2021.1972492
关键词
Lamotrigine; humanised-liver mouse; NOG-TKm30 mouse; Hu-Liver cells; N-glucuronidation
资金
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED [21am0101121j0005]
- METI artificial intelligence-based substance hazard integrated prediction system project in Japan
- Japan Society for the Promotion of Science [20K06463]
- Grants-in-Aid for Scientific Research [20K06463] Funding Source: KAKEN
Lamotrigine metabolism in humanised-liver mice showed similarities to humans, while differences were observed in mice. The study indicates that humanised-liver mice may be a valuable animal model for studying UGT1A4-mediated lamotrigine metabolism.
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). 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. 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. 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. These results suggest that humanised-liver mice may be a suitable animal model for studying the UGT1A4 mediated-lamotrigine metabolism.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据