Comparative effects of amphetamine and fenfluramine on lipid biosynthesis and absorption in the rat

Abstract

The effects of amphetamine and fenfluramine on lipid biosynthesis and intestinal absorption of triglycerides in the rat were observed independently of the anorectic activity of these drugs. Amphetamine and fenfluramine significantly reduced de novo lipogenesis and cholesterogenesis from 3H 2O and [ 14C] alanine in isolated hepatocytes. Fenfluramine was four times more potent an inhibitor than amphetamine. At high concentrations (above 2 mM), fenfluramine inhibited 14CO 2production from [ 14C] alanine in isolated hepatocytes while amphetamine stimulated 14CO 2 production at all concentrations tested (0.25 to 8 mM). Lipogenesis in liver and adipose tissue was not reduced in vivo by the acute administration of amphetamine. It, however, reduced lipogenesis in the small intestine. Fenfluramine significantly depressed in vivo lipogenesis in liver, small intestine and adipose tissue at 10 and 20 mg/kg, i.p. Hepatic cholesterogenesis was depressed significantly in vivo by both drugs. Fenfluramine increased serum free fatty acids while amphetamine produced no change. Triglycerides were increased significantly by fenfluramine only. Serum cholesterol and phospholipids were unchanged. Fenfluramine at 40 and 60 mg/kg, p.o., diminished significantly the intestinal absorption of triglycerides and depressed the accumulation of lipid in the liver. Analogous effects were not observed with amphetamine. Amphetamine was a weak inhibitor of rat pancreatic lipase (EC 3.1.1.3) ( K i = 21 mM) and fenfluramine was a stronger inhibitor ( K i = 3.3 mM).