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

Abstract

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.

Figure 1

Magnitude and time course of cocaine-like discriminative stimulus produced by the training dose of 0.32 mg/kg cocaine in rhesus monkeys (n=5). Effects of saline tests are also shown for comparison. Top Ordinate: percent cocaine-appropriate responding. Bottom Ordinate: rates of responding in responses per second. Abscissae: time in min after administration (log scale). Symbols above “S” and “C” represent the group averages SEM for all training sessions preceding test sessions when the saline- and cocaine-associated keys were correct, respectively. Filled symbols represent statistical significance (p < 0.05) within a given time point compared to experimental sessions when saline was administered (dotted line).

Figure 2

Time course of the cocaine-like discriminative stimulus of (+)-phenmetrazine (0.1 – 1.0 mg/kg, Panel A), (−)-phenmetrazine (0.32 – 10.0 mg/kg, Panel B), (+)-phendimetrazine (0.32 – 10.0 mg/kg, Panel C), and (−)-phendimetrazine (1.0 – 32.0 mg/kg, Panel D) in rhesus monkeys (n=5). All points represent the mean SEM of 5 monkeys except where indicated by numbers in parentheses in the top panels. In these cases, responding was eliminated in some monkeys, and the parenthetic number indicates the number of subjects responding at levels sufficient to contribute to the data point. Other details as in Figure 1.

Figure 3

Plasma levels (nM) of phenmetrazine and phendimetrazine as a function of time after administration of (+)-phenmetrazine (0.1 – 1.0 mg/kg; Panel A), (+)-phendimetrazine (0.32 – 3.2 mg/kg; Panels B, C) in rhesus monkeys (n=5). Ordinates: plasma levels in nM (log scale). Abscissae: time in min after drug administration (linear scale).

Figure 4

Correlation between plasma (+)-phenmetrazine levels and percent cocaine-appropriate responding as a function of time after (+)-phenmetrazine administration in rhesus monkeys (n=5). Ordinates: percent cocaine-appropriate responding. Abscissae: plasma (+)-phenmetrazine levels in nM (log scale). Different symbols represent different doses of (+)-phenmetrazine in individual monkeys. In the presence of a significant correlation, the effective concentration, in nM, that produced 50% cocaine-appropriate responding (EC50) value was calculated using linear regression. Each panel shows data for a different time after (+)-phenmetrazine administration, and this time is shown in the upper left corner of each panel.

Figure 5

EC50 values for (+)-phenmetrazine (Panel A) and (+)-phendimetrazine (Panel B) as a function of time (min) after phenmetrazine or phendimetrazine administration in rhesus monkeys. EC50 value in nM (log scale). Abscissae: time in min after administration of phenmetrazine (open circles) or phendimetrazine (half-filled circles) (log scale). EC50 values were only calculated in the presence of a significant correlation; see Supplemental Tables 2 and 3 for correlation results. All points show mean data from 5 monkeys.