title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. mbanks7@vcu.edu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fennell
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Snyder
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D009025:Morpholines / Q000097:blood* / Q000494:pharmacology; D010633:Phenmetrazine / Q000097:blood* / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology*
chemical_list: D009025:Morpholines; C100294:phendimetrazine; D003042:Cocaine; D010633:Phenmetrazine