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%. Co-administration 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). Further, 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 significantly 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 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 h} was 2.1 times greater and the Tmax occurred 1.1 h 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.