van Heek M, Farley C, Compton D S, Hoos L, Alton K B, Sybertz E J, Davis H R
CNS/CV Pharmacology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Br J Pharmacol. 2000 Apr;129(8):1748-54. doi: 10.1038/sj.bjp.0703235.
Previous studies described the metabolism-based discovery of a potent, selective inhibitor of intestinal absorption of cholesterol, SCH58235 (Ezetimibe). Here we demonstrate that the phenolic glucuronide (SCH60663) of SCH58235, was more potent at inhibiting cholesterol absorption in rats than SCH58235, when administered by the intraduodenal route. To understand the increased potency of the glucuronide, the metabolism and distribution of SCH58235 and SCH60663 were studied in bile duct-cannulated rats. One minute after intraduodenal delivery of SCH58235, significant levels of compound were detected in portal plasma; >95% was glucuronidated, indicating that the intestine was metabolizing SCH58235 to its glucuronide. When intraduodenally delivered as SCH58235, the compound was glucuronidated, moved through the intestinal wall, into portal plasma, through the liver, and into bile. However, when delivered as SCH60663, >95% of the compound remained in the intestinal lumen and wall, which may explain its increased potency. Significant inhibition of cholesterol absorption and glucuronidation of SCH58235 occurred when SCH58235 was intravenously injected into bile duct-cannulated rats. Autoradiographic analysis demonstrated that drug related material was located throughout the intestinal villi, but concentrated in the villus tip. These data indicate that (a) SCH58235 is rapidly metabolized in the intestine to its glucuronide; (b) once glucuronidated, the dose is excreted in the bile, thereby delivering drug related material back to the site of action and (c) the glucuronide is more potent than the parent possibly because it localizes to the intestine. Taken together, these data may explain the potency of SCH58235 in the rat (ID(50) = 0.0015 mg kg(-1)) and rhesus monkey (ID(50) = 0.0005 mg kg(-1)).
先前的研究描述了基于代谢发现的一种强效、选择性胆固醇肠道吸收抑制剂SCH58235（依泽替米贝）。在此我们证明，当通过十二指肠内途径给药时，SCH58235的酚葡糖苷酸（SCH60663）在抑制大鼠胆固醇吸收方面比SCH58235更有效。为了解葡糖苷酸效力增强的原因，我们在胆管插管大鼠中研究了SCH58235和SCH60663的代谢及分布情况。在十二指肠内给予SCH58235一分钟后，门静脉血浆中检测到显著水平的该化合物；超过95%被葡糖醛酸化，表明肠道正在将SCH58235代谢为其葡糖苷酸。当以SCH58235的形式经十二指肠内给药时，该化合物被葡糖醛酸化，穿过肠壁进入门静脉血浆，再通过肝脏进入胆汁。然而，当以SCH60663的形式给药时，超过95%的化合物留在肠腔和肠壁中，这可能解释了其效力增强的原因。当将SCH58235静脉注射到胆管插管大鼠体内时，发生了对胆固醇吸收的显著抑制以及SCH58235的葡糖醛酸化。放射自显影分析表明，药物相关物质遍布肠绒毛，但集中在绒毛顶端。这些数据表明：（a）SCH58235在肠道中迅速代谢为其葡糖苷酸；（b）一旦被葡糖醛酸化，该剂量就会随胆汁排出，从而将药物相关物质送回作用部位；（c）葡糖苷酸可能比母体更有效，因为它定位于肠道。综合来看，这些数据可能解释了SCH58235在大鼠（半数抑制剂量（ID(50)） = 0.0015 mg·kg⁻¹）和恒河猴（ID(50) = 0.0005 mg·kg⁻¹）中的效力。
