Effects of L-fenfluramine on rat liver drug-metabolizing enzymes

The kinetics of l-fenfluramine (l-F) are dose-dependent in man and rats, suggesting self-inhibition of metabolism and saturation of microsomal enzymes. Possible alterations in the oxidative metabolism of model drug substrates were therefore evaluated in rats given l-F orally (12.5 mg/kg). The compound slightly impaired the clearance of antipyrine but had no effect on the kinetics of highly extracted compounds such as lidocaine. l-F did not alter the hepatic content of the main components of the cytochrome P-450 system and did not affect the in vitro metabolism of enzyme activity markers, even after daily doses of 12.5 mg/kg. It was concluded that at doses with dose-dependent behaviour l-F may impair clearance of drugs such as antipyrine and that this interaction most probably occurs through inhibition of specific isoenzymes involved in the metabolism of the test substrate.