Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function.
1. Ezetimibe potently inhibits the transport of cholesterol across the intestinal wall, thereby reducing plasma cholesterol in preclinical animal models of hypercholesterolemia. The effect of ezetimibe on known absorptive processes was determined in the present studies. 2. Experiments were conducted in the hamster and/or rat to determine whether ezetimibe would affect the absorption of molecules other than free cholesterol, namely cholesteryl ester, triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid. In addition, to determine whether exocrine pancreatic function is involved in the mechanism of action of ezetimibe, a biliary anastomosis model, which eliminates exocrine pancreatic function from the intestine while maintaining bile flow, was established in the rat. 3. Ezetimibe reduced plasma cholesterol and hepatic cholesterol accumulation in cholesterol-fed hamsters with an ED(50) of 0.04 mg kg(-1). Utilizing cholesteryl esters labelled on either the cholesterol or the fatty acid moiety, we demonstrated that ezetimibe did not affect cholesteryl ester hydrolysis and the absorption of fatty acid thus generated in both hamsters and rats. The free cholesterol from this hydrolysis, however, was not absorbed (92 - 96% inhibition) in the presence of ezetimibe. Eliminating pancreatic function in rats abolished hydrolysis of cholesteryl esters, but did not affect the ability of ezetimibe to block absorption of free cholesterol (-94%). Ezetimibe did not affect the absorption of triglyceride, ethinylestradiol, progesterone, vitamins A and D, and taurocholic acid in rats. 4. Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would.
van Heek
M
M
CNS/CV Pharmacology, Schering-Plough Research Institute, Kenilworth, New Jersey, NJ 07033, USA. margaret.vanheek@spcorp.com
Farley
C
C
Compton
D S
DS
Hoos
L
L
Davis
H R
HR
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001662:Biliary Tract Surgical Procedures / Q000379:methods; D002250:Carbon Radioisotopes; D002784:Cholesterol / Q000097:blood / Q000493:pharmacokinetics*; D002788:Cholesterol Esters / Q000493:pharmacokinetics; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000493:pharmacokinetics; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics; D000069438:Ezetimibe; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010179:Pancreas / Q000502:physiology*; D011374:Progesterone / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D014304:Triolein / Q000493:pharmacokinetics; D014316:Tritium; D014801:Vitamin A / Q000493:pharmacokinetics; D014807:Vitamin D / Q000493:pharmacokinetics
D000924:Anticholesteremic Agents; D001384:Azetidines; D002250:Carbon Radioisotopes; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D014316:Tritium; D014801:Vitamin A; D014304:Triolein; D014807:Vitamin D; C014409:cholesteryl oleate; D004997:Ethinyl Estradiol; D011374:Progesterone; D013656:Taurocholic Acid; D002784:Cholesterol; D000069438:Ezetimibe