Key Laboratory of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
J Pharm Sci. 2009 Nov;98(11):4391-401. doi: 10.1002/jps.21721.
Present study was designed to explore roles of metabolic clearance in the disposition of berberine (BBR) in rats, with a focus on oxidative metabolism and subsequent glucuronidation. Plasma from rats after intravenous administration of BBR was collected to identify and quantify BBR and its major metabolites. The major circulating metabolites of BBR were oxidative metabolites M1 (via demethylation) and M2 (via demethylenation) and their corresponding glucuronides, with M2-glucuronide approximately 24-fold higher than M1-glucuronide. Incubations with rat liver microsomes were conducted to examine formation kinetics of two oxidative metabolites-M1 and M2, and depletion kinetics of M1 and M2, leading to the formation of glucuronide conjugates. Efforts were also made to examine roles of key CYPs and UGTs isoforms responsible for BBR metabolism using known chemical inhibitors and/or substrates. In vitro, the formation of M1 and M2 were comparable and multiple CYP enzymes were involved. In contrast, the glucuronidation of M2 was much faster than that of M1. Inhibition studies using well-characterized UGT substrates suggested both M1 and M2 could be glucuronidated by UGT1A1 and UGT2B1 while M2 glucuronidation was favored by UGT1A1. In summary, oxidative demethylenation and the subsequent glucuronidation were the major metabolic pathways of BBR in rats.
本研究旨在探讨代谢清除在大鼠体内小檗碱（BBR）处置中的作用，重点关注氧化代谢及其随后的葡萄糖醛酸化。静脉给予 BBR 后的大鼠血浆用于鉴定和定量 BBR 及其主要代谢物。BBR 的主要循环代谢物为氧化代谢物 M1（通过去甲基化）和 M2（通过去亚甲基化）及其相应的葡萄糖醛酸化物，其中 M2-葡萄糖醛酸化物约比 M1-葡萄糖醛酸化物高 24 倍。使用大鼠肝微粒体进行孵育以研究两种氧化代谢物 M1 和 M2 的形成动力学以及 M1 和 M2 的耗竭动力学，从而形成葡萄糖醛酸缀合物。还努力使用已知的化学抑制剂和/或底物来检查负责 BBR 代谢的关键 CYP 和 UGT 同工酶的作用。体外，M1 和 M2 的形成相当，涉及多种 CYP 酶。相比之下，M2 的葡萄糖醛酸化速度比 M1 快得多。使用经过良好表征的 UGT 底物进行的抑制研究表明，M1 和 M2 均可被 UGT1A1 和 UGT2B1 葡萄糖醛酸化，而 M2 葡萄糖醛酸化则有利于 UGT1A1。总之，氧化去亚甲基化和随后的葡萄糖醛酸化是大鼠体内 BBR 的主要代谢途径。
