[Hypolipidemic action of F-1394, an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, in high-fat diet fed beagle dogs]

Yakugaku Zasshi. 1997 Apr;117(4):233-41. doi: 10.1248/yakushi1947.117.4_233.
[Article in Japanese]

Abstract

In the present study, we investigated the hypolipidemic effect of F-1394, a potent and selective inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT), in dogs fed with a high-fat diet consisting of regular foods, 5% cholesterol and 16% fat. The serum cholesterol levels in dogs reached the steady-state 1 week after the start of feeding of a high-fat diet and were about 2-fold greater than those in normolipidemic dogs. Graded administration of the doses of F-1394 (1-30 mg/kg/d) to the dogs fed with a high-fat diet prevented the elevation of serum cholesterol levels. In the hyperlipidemic dogs fed with a high-fat diet for 14 d before the start of the administration of F-1394, the oral administration of F-1394 at a dose of 1, 3 or 10 mg/kg/d for 21 d reduced the serum cholesterol levels in a dose-dependent manner. The estimated ID50 value was 7.2 +/- 0.3 mg/kg/d p. o. (12.1 +/- 0.5 mol/kg/d p. o.). F-1394 did not affect the body weight and no diarrhea was observed by the administration of F-1394. F-1394 at a dose of 10 mg/kg/d or more also significantly inhibited the increase of serum triglyceride levels 3 h after the feeding of high-fat diet. These results suggest that F-1394 inhibits the ACAT activity in the canine small intestine and, subsequently, the inhibition of ACAT activity contributes much to the prevention of cholesterol absorption via the gut, resulting in a decrease in serum cholesterol levels in the dogs fed with high-fat diet. Furthermore, F-1394 may also have an inhibitory effect on the triglyceride absorption via the gut, and the therapeutical use for postprandial hypertriglyceridemia is expected.

Publication types

  • English Abstract

MeSH terms

  • Animals
  • Cholesterol / blood
  • Cyclohexanes / pharmacology*
  • Cyclohexanes / therapeutic use*
  • Depression, Chemical
  • Dietary Fats / administration & dosage
  • Dioxanes / pharmacology*
  • Dioxanes / therapeutic use*
  • Dogs
  • Dose-Response Relationship, Drug
  • Hyperlipidemias / blood
  • Hyperlipidemias / drug therapy*
  • Male
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Triglycerides / blood

Substances

  • Cyclohexanes
  • Dietary Fats
  • Dioxanes
  • F 1394
  • Triglycerides
  • Cholesterol
  • Sterol O-Acyltransferase