Comparative biodisposition and metabolism of¹⁴C-(±)-fenfluramine in mouse, rat, dog and man

Abstract

1. The comparative metabolism of fenfluramine was investigated in mouse, rat, dog and man following a single oral dose of 14C-(+/-)-fenfluramine hydrochloride (1 mg/kg), and also in rat after eight consecutive 12-h subcutaneous doses (24 mg/kg). 2. Main route of excretion of radioactivity in all species and at all doses was into urine (> 80%), with only minor amounts of radioactivity found in faeces. 3. From all species examined a total of 11 metabolites were observed in urine and plasma by t.l.c. and h.p.l.c. analysis and no metabolite was present in the plasma which was not present in urine. 4. All species dealkylate fenfluramine to the active metabolite norfenfluramine, to a relative greater or lesser extent, with plasma metabolic ratios (norfenfluramine/fenfluramine) showing inter-animal variation (rat >> dog >> mouse = man). 5. These differences are due to the efficient deamination of both compounds to polar inactive metabolites in man, with less dealkylation and lower plasma levels of norfenfluramine compared with the other species studied. 6. In conclusion, major species differences in the metabolism of (+/-)-fenfluramine, both qualitative and quantitative were observed, and no one species had a similar metabolic profile to that found in man.

Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice

“…In the rat, recent studies have used selective 5-HT 1B and 5-HT 2C receptor antagonists and shown that 5-HT 1B receptor activation plays no role in the hypophagia induced by d-fenfluramine, or its metabolite d-norfenfluramine, whereas antagonism of 5-HT 2C receptors produced an almost complete reversal of the hypophagic effect of either drug (Vickers et al 2001a). However, there are significant differences in the metabolism of fenfluramine between rats and mice (Caccia et al 1982;Marchant et al 1992) that might predict a different pattern of results in the two species. In particular, the ratio of plasma d-fenfluramine to d-norfenfluramine is much higher in the mouse than in the rat.…”

Fenfluramine-induced pulmonary vasoconstriction: role of serotonin receptors and potassium channels

“…It could be partly related to the binding of fenfluramine in plasma (ϳ40%) (38). Also, the metabolism of fenfluramine is much faster in rats than in humans (22). There are data supporting species differences in the density of 5-HT receptors (19,35).…”

Serotonergic drugs and valvular heart disease

“…In humans and animals receiving systemic (±)-fenfluramine, circulating concentrations of (+)-and (−)-norfenfluramine are similar to or greater than concentrations of fenfluramine itself 25, 26. Moreover, stereoisomers of (±)-fenfluramine and (±) norfenfluramine cross the blood-brain barrier to accumulate in the central nervous system.…”