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- Title
Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats.
- Authors
van Heek, Margaret; Farley, Constance; Compton, Douglas S.; Hoos, Lizabeth M.; Smith-Torhan, April; Davis, Harry R.
- Abstract
1 Ezetimibe (1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphe-nyl)-2-azetidinone) and its analog SCH48461 are potent and selective cholesterol absorption inhibitors that inhibit the transport of cholestrol across the intestinal wall, thereby lowering plasma cholesterol. 2 After a dose response for ezetimibe in rats was established, experiments were conducted to determine whether acute administration could alter hepatic or intestinal cholesterol synthesis. To determine whether this class of intestinal cholesterol absorption inhibitors could discriminate between newly synthesized cholesterol in the intestine versus exogenously administered cholesterol, rats were intraduodenally dosed with [SUP14]C-cholesterol and [SUP3]H-mevalonate, and mesenteric lymph was analyzed for radiolabeled cholesterol and cholesteryl ester content. 3 Ezetimibe attenuated diet-induced hypercholesterolemia 60-94% at doses of 0.1-3 mg kg[SUP-1] in rats. A single administration of ezetimibe did not have a direct effect on intestinal or hepatic cholesterol synthesis, while ketoconazole significantly inhibited cholesterol synthesis after a single dose. The ezetimibe analog, SCH48461, inhibited the movement of exogenously administered cholesterol into lymph, but did not affect the appearance of newly synthesized cholesterol into lymph. 4 These data suggest that this class of cholesterol absorption inhibitors does discriminate by blocking the movement of exogens cholesterol in the enterocyte before it reaches the intracellular cholesterol pool to be incorporated into intestinal lipoproteins, without affecting the incorporation of newly synthesized cholesterol into intestinal lipoproteins.
- Subjects
ENZYME inhibitors; CHOLESTEROL; HEPATIC artery; INTESTINES; RATS
- Publication
British Journal of Pharmacology, 2003, Vol 138, Issue 8, p1459
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705187