Reduced cholesterol absorption in hamsters by crilvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
Crilvastatin, a new drug from the pyrrolidone family, has been previously shown to inhibit the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, in vitro and in vivo, to reduce the absorption of dietary cholesterol and to stimulate the activity of cholesterol 7 alpha-hydroxylase in the rat. The aim of this study was to evaluate the effects of crilvastatin on cholesterol and bile acid metabolism in the hamster. In hamsters fed on a lithogenic diet for 8 weeks, crilvastatin treatment (200 mg/day per kg body weight) did not change plasma lipid levels, failed to improve bile parameters and did not prevent gallstone formation. In hamsters fed on a basal cholesterol-rich (0.2%) diet for 8 weeks, crilvastatin at the same dose reduced the cholesterol level in the plasma by 20%, with a decrease of both low-density and high-density lipoprotein cholesterol. The drug did not significantly stimulate the biliary secretion of bile acids but significantly decreased the activity of acyl coenzyme A:cholesterol acyltransferase in the small intestine by 64%. This effect was enhanced when cholestyramine, a bile acid-sequestering resin, was given in combination with crilvastatin. Crilvastatin alone did not change the activity of cholesterol 7 alpha-hydroxylase in the liver, despite the marked reduction in both hepatic cholesterogenesis and intestinal absorption of dietary cholesterol (the absorption coefficient was 44 +/- 2% in treated hamsters vs. 61 +/- 7% in controls).
Hajri
T
T
Laboratoire de Physiologie de la Nutrition, Université Paris-Sud, Orsay, France.
Chanussot
F
F
Férézou
J
J
Riottot
M
M
Lafont
H
H
Laruelle
C
C
Lutton
C
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001646:Bile / Q000737:chemistry / Q000187:drug effects; D001647:Bile Acids and Salts / Q000378:metabolism; D002769:Cholelithiasis / Q000517:prevention & control; D002791:Cholesterol, Dietary / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000494:pharmacology; D006224:Cricetinae; D004357:Drug Synergism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007408:Intestinal Absorption / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D002792:Cholestyramine Resin; C081831:crilvastatin; D011392:Proline; D002785:Sterol O-Acyltransferase