title: Role of d-amphetamine and d-methamphetamine as active metabolites of benzphetamine: Evidence from drug discrimination and pharmacokinetic studies in male rhesus monkeys.
abstract: Benzphetamine is a Schedule III anorectic agent that is a prodrug for d-amphetamine and d-methamphetamine and may have utility as an "agonist" medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic-pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine-like discriminative stimulus effects were compared for benzphetamine (10-18mg/kg, intramuscular (IM)) and d-amphetamine (0.032-0.32mg/kg, IM) in monkeys (n=3-4) trained to discriminate IM cocaine (0.32mg/kg) from saline in a two-key food-reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d-methamphetamine and/or d-amphetamine levels for correlation with behavioral effects. d-Amphetamine produced dose-dependent, time-dependent, and full cocaine-like effects, i.e. ≥90% cocaine-appropriate responding, in all monkeys without altering response rates. The time course of d-amphetamine's cocaine-like discriminative stimulus effects correlated with plasma d-amphetamine levels. Benzphetamine was 180-fold less potent than d-amphetamine and produced full cocaine-like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d-methamphetamine (peak at 100min) and d-amphetamine (peak at 24h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d-methamphetamine or d-amphetamine. These results suggest that benzphetamine yields d-amphetamine and d-methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d-amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment.
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: matthew.banks@vcuhealth.org.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Pharmacology & Toxicology, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Snyder
authors.affiliation: Department of Pharmacology & Toxicology, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fennell
authors.affiliation: Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001589:Benzphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001589:Benzphetamine; D008694:Methamphetamine; D003913:Dextroamphetamine
keywords: Benzphetamine; Cocaine; Discrimination; Pharmacodynamic; Pharmacokinetic; Rhesus monkey