The effects of cyclic imides on lipid absorption from the intestine and on bile lipids and bile acids of Sprague Dawley rats.
The cyclic imides, o-(N-phthalimido)acetophenone, 2,3-dihydrophthazine-1,4-dione and N(4-methyl phenyl)diphenimide, were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent at 20 mg/kg/day orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic in rats. The three agents did decrease cholesterol and cholic acid absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha hydroxylase, sn-glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase were reduced. However, the cyclic imides did not accelerate HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, in a manner which would accelerate biliary cholesterol excretion. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360.
Reynolds
D J
DJ
Wong
O T
OT
Simlot
S
S
D000818:Animals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D002784:Cholesterol / Q000493:pharmacokinetics; D019826:Cholic Acid; D002793:Cholic Acids / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007094:Imides / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001647:Bile Acids and Salts; D002793:Cholic Acids; D000960:Hypolipidemic Agents; D007094:Imides; D002784:Cholesterol; D019826:Cholic Acid