Role of phenmetrazine as an active metabolite of phendimetrazine: evidence from studies of drug discrimination and pharmacokinetics in rhesus monkeys.

BACKGROUND: Monoamine releasers such as d-amphetamine that selectively promote release of dopamine/norepinephrine versus serotonin are one class of candidate medications for treating cocaine dependence; however, their clinical utility is limited by undesirable effects such as abuse liability. Clinical utility of these compounds may be increased by development of prodrugs to reduce abuse potential by slowing onset of drug effects. This study examined the behavioral and pharmacokinetic profile of the Schedule III compound phendimetrazine, which may serve as a prodrug for the N-demethylated metabolite and potent dopamine/norepinephrine releaser phenmetrazine. METHODS: Monkeys (n = 5) were trained in a two-key food-reinforced discrimination procedure to discriminate cocaine (0.32 mg/kg, IM) from saline, and the potency and time course of cocaine-like discriminative stimulus effects were determined for (+)-phenmetrazine, (-)-phenmetrazine, (+)-phendimetrazine, (-)-phendimetrazine, and (±)-phendimetrazine. Parallel pharmacokinetic studies in the same monkeys examined plasma phenmetrazine and phendimetrazine levels for correlation with cocaine-like discriminative stimulus effects. RESULTS: Both isomers of phenmetrazine, and the racemate and both isomers of phendimetrazine, produced dose- and time-dependent substitution for the discriminative stimulus effects of cocaine, with greater potency residing in the (+) isomers. In general, plasma phenmetrazine levels increased to similar levels after administration of behaviorally active doses of either phenmetrazine or phendimetrazine. CONCLUSIONS: These results support the hypothesis that phenmetrazine is an active metabolite that contributes to the effects of phendimetrazine. However, behavioral effects of phendimetrazine had a more rapid onset than would have been predicted by phenmetrazine levels alone, suggesting that other mechanisms may also contribute.

Comparative metabolism of the amphetamine drugs of dependence in man and monkeys.

The use of animal models to study drug dependence and tolerance requires that the species used metabolizes the drugs like man, a condition frequently not fulfilled by non-primate species. The metabolic fate of several amphetamine drugs, namely amphetamine, norephedrine, chlorphentermine and phenmetrazine, in the rhesus monkey and the tamarin and two non-primate species has been investigated and compared to that found for man. The findings show that the two primate species metabolize these drugs in a manner similar to that in man.

The fate of amphetamine and norephedrine in the Tamarin monkey compared with man.

When [14C] (+/-)-amphetamine sulphate (0.3 mg/kg) was injected into Tamarin monkeys, some 70-80% of the 14C was excreted in the urine in 24 hours. Some 75% of the 24-hour excretion was unchanged drug, 7% was free and conjugated benzoic acid and 7% was hydroxylated in the aromatic ring to give mainly 4-hydroxyamphetamine (Paredrine). With similar doses of [14C] norephedrine hydrochloride nearly 90% of the 14C was excreted in 24 hours, most of this being unchanged drug. Only 3-4% was metabolized at the side chain and there was no aromatic hydroxylation. The results were compared with those obtained earlier in man, rat, rabbit and guinea pig. Quantitatively the metabolites of amphetamine, norephedrine and preludin in the tamarin were more like those in man than in the other three species.