Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations

J Pharm Sci. 2011 Jul;100(7):2966-78. doi: 10.1002/jps.22476. Epub 2011 Jan 14.


We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Cutaneous
  • Administration, Oral
  • Animals
  • Biological Availability
  • Biotransformation
  • Brain / drug effects
  • Brain / metabolism
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / blood
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / pharmacokinetics*
  • Central Nervous System Stimulants / urine
  • Drug Interactions
  • Esterification
  • Ethanol / administration & dosage*
  • Gas Chromatography-Mass Spectrometry
  • Intestinal Absorption / drug effects
  • Isomerism
  • Male
  • Methylphenidate / administration & dosage
  • Methylphenidate / analogs & derivatives
  • Methylphenidate / blood
  • Methylphenidate / chemistry
  • Methylphenidate / pharmacokinetics*
  • Methylphenidate / urine
  • Mice
  • Mice, Inbred C57BL
  • Skin Absorption / drug effects
  • Transdermal Patch


  • Central Nervous System Stimulants
  • Methylphenidate
  • Ethanol
  • ethylphenidate