ORAL KINETICS OF DEXFENFLURAMINE AND DEXNORFENFLURAMINE IN NONHUMAN-PRIMATES

1. Large doses of dexfenfluramine in animals cause a decrease of serotoninergic markers but none of the species so far investigated shows sufficient kinetic and metabolic similarity with man to be a valid model for safety studies. The plasma kinetics of dexfenfluramine and its active metabolite dexnorfenfluramine were therefore studied in baboon, rhesus and cynomolgus monkeys given dexfenfluramine hydrochloride orally (2 mg/kg) in order to investigate whether any of these primates have a biodisposition particularly similar to man. 2. The drug was rapidly N-deethylated to dexnorfenfluramine achieving comparatively low mean maximum plasma levels (C-max) of 12-14 ng/ml in all primates, and rapidly disappeared thereafter with half-lives (t(1/2)) ranging from 2 to 3 h in the baboon and rhesus monkey to 6 h in the cynomolgus monkey. Its normetabolite reached higher mean C-max (52-97 ng/ml) and the t(1/2)'s were longer, varying from about ii h in the rhesus monkey to 22 h in the cynomolgus monkey. The metabolite-to-parent drug ratio (14-37), in terms of plasma area under curve (A UC), greatly exceeded that in man (< 1), being higher than in all species investigated so far. 3. Comparative repeat dose simulation in monkey and man indicated that the dosage in primates would need to be increased 10-fold to achieve comparable dexfenfluramine steady-state plasma C-max, producing nor-metabolite levels several times those in man, whilst for comparable metabolite C-max, those of the parent drug would be correspondingly too low. 4. In view of the different mechanism of action of dexfenfluramine and dexnorfenfluramine within the serotoninergic system none of these primates is therefore a suitable model for safety assessment in terms of exposure of the active moieties in comparison with man.