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.

Figure 1

Deesterification of dl-MPH to the primary metabolite ritalinic acid and the enantioselective transesterification pathway to yield l-ethylphenidate.

Figure 2

Mean (±SD) d-MPH plasma concentrations after (A) dosing with dl-MPH (0.3 mg/kg) followed by ethanol (0.6 gm/kg; (◆)); (B) dosing with ethanol followed by dl-MPH (■); or (C) dosing with dl-MPH alone (▲). Data from 19 normal MPH metabolizers.

Figure 3

Plasma concentrations of l-MPH in the poor metabolizer (upper profiles) after the following regimens: dl-MPH, then ethanol (◆); ethanol, then dl-MPH (■); dl-MPH only (▲). Corresponding mean (±SD) plasma concentrations for the 19 normal MPH-metabolizers are shown in the lower profile.