title: Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans.
abstract: Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, USA. patrickk@musc.edu
authors.forename: Kennerly S
authors.initials: KS
authors.lastname: Patrick
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Straughn
authors.forename: Owen T
authors.initials: OT
authors.lastname: Reeves
authors.forename: Hilary
authors.initials: H
authors.lastname: Bernstein
authors.forename: Guinevere H
authors.initials: GH
authors.lastname: Bell
authors.forename: Erica R
authors.initials: ER
authors.lastname: Anderson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Malcolm
mesh_terms: D000328:Adult; D019540:Area Under Curve; D043182:Carboxylesterase / Q000378:metabolism; D064699:Dexmethylphenidate Hydrochloride; D004951:Esterification; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D064699:Dexmethylphenidate Hydrochloride; D008774:Methylphenidate; D000431:Ethanol; D043182:Carboxylesterase