Premium
Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics
Author(s) -
Patrick K S,
Straughn A B,
Minhinnett R R,
Yeatts S D,
Herrin A E,
DeVane C L,
Malcolm R,
Janis G C,
Markowitz J S
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100082
Subject(s) - pharmacokinetics , methylphenidate , cmax , crossover study , pharmacodynamics , metabolite , bioavailability , ethanol , stimulant , pharmacology , chemistry , active metabolite , geometric mean , medicine , placebo , biochemistry , attention deficit hyperactivity disorder , mathematics , statistics , alternative medicine , pathology , psychiatry
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. Clinical Pharmacology & Therapeutics (2007) 81 , 346–353. doi: 10.1038/sj.clpt.6100082