The effect of previous d-amphetamine treatment on the disposition and lethality of fenfluramine in the rat.
In an earlier study, it was found that a 15-day ip postfeeding session d-amphetamine treatment rendered an apparent "tolerance" to the feed intake suppressant effects of fenfluramine. The purpose of the present study was to determine if such d-amphetamine treatment altered the disposition of fenfluramine in a way which might account for this decrement in the feed intake suppressant effect of fenfluramine. In addition, the effect of d-amphetamine on fenfluramine toxicity was also examined in an attempt to further characterize and correlate fenfluramine dispositional changes. It was found that plasma and, to some extent, brain concentrations of fenfluramine were elevated in the d-amphetamine-treated rats as compared to a saline control group. The acute, ip LD50 for fenfluramine in d-amphetamine-treated rats was 68 mg/kg (95% CI = 64.8 to 71.4), a value significantly lower than that observed in the saline-treated animals (97 mg/kg; 95% CI = 93.3 to 100.9). The overall results of this study suggest that the anorectic tolerance conferred toward fenfluramine by previous subchronic treatment with d-amphetamine does not result from decreased plasma or brain concentrations of fenfluramine. In fact, such concentrations are increased by prior d-amphetamine treatment, and this increase may in part account for the increased lethality of fenfluramine observed in these animals.
D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004347:Drug Interactions; D005277:Fenfluramine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D005277:Fenfluramine; D000661:Amphetamine