Yamamoto Takehito, Ito Kousei, Honma Masashi, Takada Tappei, Suzuki Hiroshi
Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Drug Metab Dispos. 2007 Sep;35(9):1455-8. doi: 10.1124/dmd.107.015628. Epub 2007 Jun 13.
Ezetimibe (EZE) selectively blocks intestinal cholesterol absorption by interacting with Niemann-Pick C1 Like 1 (NPC1L1). After administration, EZE is extensively metabolized in liver and intestine to its phenolic glucuronide form (EZE-G) by uridine diphosphate glucuronosyltransferases (UGTs), among which UGT1A1 and 1A3 exhibit highest activity. EZE-G is excreted into bile and undergoes extensive enterohepatic recirculation. Considering the pharmacokinetic properties of EZE and an in vitro binding study showing the high affinity binding of EZE-G to NPC1L1, glucuronidation by UGTs has been believed to be essential for the pharmacological efficacy of EZE. To study the role of glucuronidation by UGTs for the cholesterol-lowering effect of EZE, in vitro and in vivo studies were performed using Gunn rats, which hereditarily lack the expression of UGT1A enzymes. The biliary excreted amount of EZE-G was reduced by 73% up to 3 h after administration of EZE (0.3 mg/kg) in Gunn rats, which is consistent with the reduction of in vitro EZE glucuronidation activity found in liver and intestinal microsome from Gunn rats. These results indicate that the formation of EZE-G in Gunn rats is much lower than that in Wistar rats. However, in vivo study showed that 0.3 mg/kg EZE, which is the clinically relevant dose, reduced cholesterol absorption in both Wistar and Gunn rats to nearly the same degree and the dose dependence was not significantly different between Wistar and Gunn rats at the range 0.001 approximately 0.3 mg/kg. These results indicate that a deficiency of UGT1A activity does not necessarily alter the cholesterol-lowering effect of EZE in rats at therapeutic doses.
依折麦布（EZE）通过与尼曼-匹克C1样1蛋白（NPC1L1）相互作用，选择性地阻断肠道胆固醇吸收。给药后，EZE在肝脏和肠道中被尿苷二磷酸葡萄糖醛酸转移酶（UGTs）广泛代谢为其酚醛葡萄糖醛酸形式（EZE-G），其中UGT1A1和1A3表现出最高活性。EZE-G排泄到胆汁中，并经历广泛的肠肝循环。考虑到EZE的药代动力学特性以及一项体外结合研究表明EZE-G与NPC1L1具有高亲和力结合，UGTs介导的葡萄糖醛酸化被认为对EZE的药理作用至关重要。为了研究UGTs介导的葡萄糖醛酸化对EZE降胆固醇作用的影响，使用遗传性缺乏UGT1A酶表达的Gunn大鼠进行了体外和体内研究。在Gunn大鼠中，给予EZE（0.3mg/kg）后3小时内，EZE-G的胆汁排泄量减少了73%，这与在Gunn大鼠肝脏和肠道微粒体中发现的体外EZE葡萄糖醛酸化活性降低一致。这些结果表明，Gunn大鼠中EZE-G的形成远低于Wistar大鼠。然而，体内研究表明，0.3mg/kg的EZE（临床相关剂量）在Wistar大鼠和Gunn大鼠中降低胆固醇吸收的程度几乎相同，并且在0.001至0.3mg/kg范围内，Wistar大鼠和Gunn大鼠之间的剂量依赖性没有显著差异。这些结果表明，在治疗剂量下，UGT1A活性的缺乏不一定会改变EZE在大鼠中的降胆固醇作用。
