Abstract
Following oral administration of [14C]-dl-fenfluramine (60mg) to human volunteers greater than 90% of the dose was recovered in urine within three days after dosing. Metabolism was extensive. The identified metabolites were the products of N-deethylation (norfenfluramine) and deamination with subsequent side chain oxidation. The parent drug was also present. The stereoselective pharmacology of fenfluramine led to studies on the individual enantiomers (30mg of each). There was a longer plasma half-life for both total radioactivity and parent drug with [14C]-1-fenfluramine. The areas under the plasma time curve for 1-fenfluramine and 1-norfenfluramine were greater than for the d-isomers. There was no apparent enantiomeric interaction, that is, the isomers behaved as individual compounds when administered together as a racemate. Investigation of the urinary metabolites of d-fenfluramine showed a greater abundance of deaminated products and less parent compound compared with 1-fenfluramine. However, ratios of fenfluramine to norfenfluramine were the same and thus the stereoselectivity seemed to reside in the deamination stage. A definitive pharmacokinetic study with d-fenfluramine showed slight first pass metabolism, the product of which appeared not to be norfenfluramine. This observation together with the urinary metabolite ratios, indicated that d-fenfluramine could be deaminated directly without being first N-deethylated. [14C]-Benfluorex was administered orally to man, rhesus monkey, baboon, beagle dog and Wistar rat. Urinary metabolic profiles were compared and the rhesus monkey was found to bear the closest resemblence to man in this respect. The parent drug appeared to undergo total first pass hydrolysis as it could not be detected in the plasma of a human volunteer following an oral dose. In man, further metabolism mainly involved oxidation of the N-2-hydroxyethyl side chain. Norfenfluramine and a single deamination product were minor urinary metabolites, although the deamination product was quantitatively important in plasma. The plasma metabolite profile, however, suggests that the deamination product was a product of first pass metabolism. The deaminated metabolite of benfluorex was not found as a metabolite of fenfluramine indicating that the N-ethyl-substitution had influenced the deamination route as well as the overall metabolic fate of the 1-(m-trifluoro-methylphenyl)-2-aminopropane nucleus.