Mechanisms of action in the liver of crilvastatin, a new hydroxymethylglutaryl-coenzyme A reductase inhibitor.
Crilvastatin is a drug from the pyrrolidone family that had been shown to induce non-competitive inhibition of rat hydroxymethylglutaryl-coenzyme A reductase activity in vitro. The aim of this study was to evaluate the activity of crilvastatin on the hepatic metabolism of cholesterol in rats. Crilvastatin increased low density lipoprotein (LDL)-cholesterol uptake by the liver more than high density lipoprotein (HDL) uptake, thus increasing by up 30% the clearance of excess plasma cholesterol. In normolipidemic rats, crilvastatin significantly enhanced acyl coenzyme A:cholesterol acyl transferase and cholesterol 7 alpha-hydroxylase activity. In rats with a previous high cholesterolemia, crilvastatin also enhanced cholesterol 7 alpha-hydroxylase activity and did not increase liver acyl coenzyme A:cholesterol acyl transferase activity. These findings suggest that a drug such as crilvastatin could have a hypocholesterolemic effect by a mechanism other than the sole inhibition of cholesterol synthesis, possibly by stimulating cholesterol and bile salt secretion via the biliary tract in previously hypercholesterolemic rats.
INSERM, Unité 130, Marseille, France.
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Jomier
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Portugal
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Morel
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Chanussot
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010743:Phospholipids / Q000097:blood; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010743:Phospholipids; C081831:crilvastatin; D002784:Cholesterol; D011392:Proline