van Heek M, Compton D S, Davis H R
CNS/CV Biological Research, Schering-Plough Research Institute, K15-2-2600, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA.
Eur J Pharmacol. 2001 Mar 9;415(1):79-84. doi: 10.1016/s0014-2999(01)00825-1.
Ezetimibe (1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone) potently and selectively inhibits the intestinal absorption of cholesterol, thereby reducing plasma cholesterol in preclinical models of hypercholesterolemia. In rhesus monkeys fed a diet containing 375 mg/day of cholesterol, 0.1 mg/kg of ezetimibe completely prevented the doubling of plasma cholesterol normally induced under these dietary conditions (ED(50)=0.0005 mg/kg). Low-density lipoprotein cholesterol (LDL) was dose-dependently reduced, while high-density lipoprotein cholesterol (HDL) and plasma triglyceride were unchanged. A single dose of an ezetimibe analog administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction (-69%) of cholesterol in chylomicrons during the postprandial phase without affecting triglyceride content. In rhesus monkeys, apolipoprotein (apo) B(48) concentrations in chylomicrons did not differ between control and the ezetimibe analog, but apo B(100) was significantly reduced in LDL (-41%). These data indicate that these cholesterol absorption inhibitors reduce cholesterol content in chylomicrons, which indirectly leads to a decrease in LDL cholesterol and particle number.
依折麦布（1-(4-氟苯基)-(3R)-[3-(4-氟苯基)-(3S)-羟丙基]-(4S)-(4-羟苯基)-2-氮杂环丁烷酮）能有效且选择性地抑制肠道对胆固醇的吸收，从而在高胆固醇血症的临床前模型中降低血浆胆固醇水平。在喂食含375毫克/天胆固醇饮食的恒河猴中，0.1毫克/千克的依折麦布完全阻止了在这些饮食条件下通常会诱导的血浆胆固醇翻倍（半数有效剂量[ED(50)] = 0.0005毫克/千克）。低密度脂蛋白胆固醇（LDL）呈剂量依赖性降低，而高密度脂蛋白胆固醇（HDL）和血浆甘油三酯则保持不变。给喂食一顿含胆固醇餐食的食蟹猴单次服用依折麦布类似物，导致餐后阶段乳糜微粒中的胆固醇显著降低（-69%），而不影响甘油三酯含量。在恒河猴中，对照组和依折麦布类似物组乳糜微粒中的载脂蛋白（apo）B(48)浓度无差异，但LDL中的apo B(100)显著降低（-41%）。这些数据表明，这些胆固醇吸收抑制剂可降低乳糜微粒中的胆固醇含量，这间接导致LDL胆固醇和颗粒数量减少。
