title: Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics.
abstract: This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA. patrickk@musc.edu
authors.forename: K S
authors.initials: KS
authors.lastname: Patrick
authors.forename: A B
authors.initials: AB
authors.lastname: Straughn
authors.forename: R R
authors.initials: RR
authors.lastname: Minhinnett
authors.forename: S D
authors.initials: SD
authors.lastname: Yeatts
authors.forename: A E
authors.initials: AE
authors.lastname: Herrin
authors.forename: C L
authors.initials: CL
authors.lastname: DeVane
authors.forename: R
authors.initials: R
authors.lastname: Malcolm
authors.forename: G C
authors.initials: GC
authors.lastname: Janis
authors.forename: J S
authors.initials: JS
authors.lastname: Markowitz
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions; D000431:Ethanol / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010597:Pharmacogenetics; D015656:Respiratory Mechanics / Q000187:drug effects; D012727:Sex Characteristics; D013237:Stereoisomerism
chemical_list: D002492:Central Nervous System Depressants; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D000431:Ethanol; C042400:ethylphenidate