Species differences in the kinetics and metabolism of fenfluramine isomers

Caccia, S.; Ballabio, M.; Guiso, G.; Rocchetti, M.; Garattini, S.

Archives Internationales de Pharmacodynamie et de Therapie 258(1): 15-28


ISSN/ISBN: 0003-9780
PMID: 7138139
Document Number: 537
After single oral doses of racemic fenfluramine to man and animals (male CD-COBS Sprague-Dawley rat, male CD1-COBS mice and male beagle dogs) plasma and/or brain concentrations of the d- and l-isomers and their deethylated metabolite were measured by gas-liquid chromatography. In rat and mouse d-fenfluramine had a longer half-life (T 1/2) and gave a larger area under the curve (AUC) than the l-isomer. These differences were consistent with stereoselective N-deethylation of l-fenfluramine. Thus, in both species the plasma and brain AUC of the l-metabolite were double that of the d-form. In man and dog slight or no differences were seen between te kinetic and metabolic profiles of the isomers. Comparison of the plasma concentrations time curve of fenfluramine showed slower elimination in man than in the other species. The T 1/2 of the d-isomer was 2.6 hr in rat, 2.5 +/- 0.2 hr in the dog. 4.3 hr in the mouse and 17.8 +/- 0.9 hr in man. The deethylated metabolite norfenfluramine was present in plasma or brain, or both, of all the species examined as a major metabolite of the drug. At the oral doses of racemic fenfluramine tested the ration of the AUC for d-norfenfluramine to d-fenfluramine was 4.4, 2.0, 0.8, 0.3, and the dog, rat man and mouse respectively. The T 1/2 of the metabolite was longer than that of the parent drug in all these species. Similar studies with d-fenfluramine indicated that its kinetic profile was identical to that of d-fenfluramine administered in the racemic form. The l-isomer therefore does not change the absorption, distribution and metabolism of the d-isomer which should be considered as the active form.

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Species differences in the kinetics and metabolism of fenfluramine isomers