Preclinical and clinical pharmacology of a new class of lipid management agents.
Ezetimibe, the first in a new class of selective cholesterol absorption inhibitors, reduces plasma levels of low-density lipoprotein (LDL) cholesterol by selectively preventing the intestinal uptake of dietary and biliary cholesterol. Initial studies in animals show that ezetimibe lowers both serum and liver cholesterol in a dose-dependent manner without decreasing the absorption of triglycerides or fat-soluble vitamins. It also appears to function primarily as its glucuronidated derivative and, in this form, localizes almost exclusively to the intestinal mucosal cells after initial absorption and glucuronidation in the gut and liver. Preclinical studies show that ezetimibe also lowers LDL effectively, whereas studies in apolipoprotein E knockout mice show that it reduces LDL, very-low-density lipoproteins, and the formation of atherosclerotic plaque in the aorta. Because of its safety and specificity, and because its mechanism of action complements that of the statins, ezetimibe is an attractive component in combination therapy. Coadministration of ezetimibe and a statin in dogs demonstrates larger reductions in cholesterol levels than therapy with either agent alone.
Rudel
Lawrence L
LL
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
D000042:Absorption; D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001161:Arteriosclerosis / Q000378:metabolism / Q000517:prevention & control; D001384:Azetidines / Q000378:metabolism / Q000493:pharmacokinetics*; D008078:Cholesterol, LDL / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D051379:Mice; D051381:Rats
D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D000069438:Ezetimibe