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.
Conti
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Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Tridico
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RV
Duan
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Caccia
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S
D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology*; D008012:Lidocaine / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D005277:Fenfluramine; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; D006899:Mixed Function Oxygenases; D000983:Antipyrine