Mechanisms responsible for the inhibitory effects of benfluorex on hepatic intermediary metabolism.

The effects of benfluorex on hepatic intermediary metabolism have been studied using the isolated hepatocyte system. The drug inhibits the synthesis of both glucose and fatty acids by hepatocytes. Evidence is obtained that hepatocytes rapidly split benfluorex into benzoic acid and 1-(3-trifluoromethylphenyl)-2-[N-(2-hydroxyethyl)amino]propane (THEP). Comparison of the effects of the parent compound with the effects of THEP and benzoic acid on gluconeogenesis and on fatty acid synthesis indicates that different metabolites of the drug are responsible for its various actions: THEP inhibits gluconeogenesis, whereas benzoic acid inhibits fatty acid synthesis. The latter pathway appears to be inhibited at two sites: mitochondrial pyruvate uptake is inhibited by benfluorex itself, whereas fatty acid synthase is inhibited by benfluorex-derived benzoic acid.