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. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2011 October 6. RESULTS Human subjectsTwenty research subjects (10 men aged 23-40 years: mean (±SD) 28.8 (5.3) years, weight 82.2 (10.5) kg, eight white, one black, one Hispanic; and 10 women aged 23-35 years: mean 28.7 (4.4) years, weight 65.2 (8.4) kg, nine white, one black, completed the entire protocol. One additional subject declined further participation after her first visit, citing discomfort with blood sampling. This subject was replaced with another female volunteer to ensure 10 of each sex completed the study. No adverse events occurred that were attributable to MPH, ethanol, or a combination thereof. All vital signs remained within normal parameters. Finally, no subject had any clinically significant findings on poststudy "exit" laboratory tests. (Figure 3). MPH-ethanol pharmacokinetic interactions Sex differences in d-MPH-ethanol pharmacokineticsThe mean (SD) extent of exposure (AUC) of d-MPH was significantly (P=0.042) greater in men (93.4 (25.3) ng h/ml) than i...

The psychostimulant dl-methylphenidate (MPH) remains the most common drug therapy in child and adolescent psychiatry for the treatment of attention-deficit-hyperactivity disorder (ADHD). Evidence of a dopaminergic basis both for the actions of MPH and for the underlying neuropathology in ADHD continues to mount. Advances in the biopharmaceutics of MPH have been conspicuous. Novel approaches to formulation design have resulted in new MPH delivery options to overcome the short-term actions of both immediate-and sustained-release MPH. New modified-release MPH products offer the convenience of once-daily administration while providing extended absorption profiles that better mimic those of standard schedules of immediate-release MPH (i.e., the absorption phase of MPH better correlates with improved behavioral response than does the elimination phase). The oral bioavailability of MPH in females may be lower than in males. The l-MPH isomer exhibits only negligible oral bioavailability and, further, possesses little intrinsic activity at the dopamine transporter. This notwithstanding, a single-isomer d-MPH immediate-release product is now available for dosing recommended at one-half that of dl-MPH.

dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). The predominantly dopaminergic mechanism of the psychostimulant actions has become more clearly defined. Neuroimaging and genetic studies are revealing the underlying neuropathology in ADHD. Novel extended-release (ER) MPH formulations now offer drug delivery options to overcome both the short-term actions of immediate-release (IR) MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS (Alza), Diffucaps (Eurand) and SODAS (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH. The pharmacodynamics of the separate MPH enantiomers is in the process of further neuropharmacological characterisation. It is well established that dl-MPH undergoes marked stereoselective metabolism. Although l-MPH exhibits only minimal oral absorption, it may preferentially penetrate the brain, and interacts with ethanol to form the metabolite ethylphenidate. The newly approved resolved enantiomer product d-MPH is now available in an IR formulation, and when administered at one-half the dose to that of the racemate, is purported to produce a longer duration of clinical effect, despite essentially identical pharmacokinetics. A long-acting formulation of d-MPH, which employs the SODAS technology, is in the advanced stages of clinical development.

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