Drug Clinical Trial Institution, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.
J Pharm Pharmacol. 2021 Mar 6;73(3):388-397. doi: 10.1093/jpp/rgaa059.
To determine the kinetics of the formation of 10,11-dihydro-10-hydroxy-carbazepine (MHD)-O-glucuronide in human liver microsomes (HLMs), human intestine microsomes (HIMs), human kidney microsomes (HKMs) and recombinant human UDP-glucuronosyltransferase (UGTs), and identify the primary UGT isoforms catalyzing the glucuronidation of MHD.
The kinetics of the glucuronidation of MHD was determined in HLMs, HIMs as well as HKMs. Screening assays with 13 recombinant human UGTs, inhibition studies and correlation analysis were performed to identify the main UGTs involved in the glucuronidation of MHD.
MHD-O-glucuronide was formed in HLMs, HIMs as well as HKMs, HLMs showed the highest intrinsic clearance of MHD. Among 13 recombinant human UGTs, UGT2B7 and UGT1A9 were identified to be the principal UGT isoforms mediating the glucuronidation of MHD, while UGT1A4 played a partial role. In addition, inhibition studies and correlation analysis further confirmed that UGT2B7 and UGT1A9 participated in the formation of MHD-O-glucuronide.
MHD could be metabolized by UGTs in the liver, intestine and kidney, and the hepatic glucuronidation was the critical metabolic pathway. UGT2B7 and UGT1A9 were the primary UGT isoforms mediating the formation of MHD-O-glucuronide in the liver.
在人肝微粒体（HLMs）、人肠微粒体（HIMs）、人肾微粒体（HKMs）和重组人 UDP-葡糖醛酸基转移酶（UGTs）中确定 10,11-二氢-10-羟基卡马西平（MHD）-O-葡糖苷酸形成的动力学，并鉴定催化 MHD 葡糖醛酸化的主要 UGT 同工酶。
在 HLMs、HIMs 和 HKMs 中测定 MHD 的葡糖醛酸化动力学。通过 13 种重组人 UGTs 的筛选试验、抑制研究和相关分析，鉴定参与 MHD 葡糖醛酸化的主要 UGT。
MHD-O-葡糖苷酸在 HLMs、HIMs 和 HKMs 中形成，HLMs 显示出最高的 MHD 内在清除率。在 13 种重组人 UGT 中，鉴定出 UGT2B7 和 UGT1A9 是介导 MHD 葡糖醛酸化的主要 UGT 同工酶，而 UGT1A4 起部分作用。此外，抑制研究和相关分析进一步证实 UGT2B7 和 UGT1A9 参与了 MHD-O-葡糖苷酸的形成。
MHD 可被肝、肠和肾中的 UGTs 代谢，肝内葡糖醛酸化是关键的代谢途径。UGT2B7 和 UGT1A9 是介导 MHD-O-葡糖苷酸形成的主要肝 UGT 同工酶。
