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%. Coadministration 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). Furthermore, 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 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 area under the curve (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 AUC0.5–2 hours was 2.1 times greater and the time to maximum concentration (Tmax) occurred 1.1 hours 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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant RO1AA016707]; the Medical University of South Carolina’s Clinical & Translational Research Center with support from the National Institutes of Health [Grant MO1RR01070-18]; and the National Institutes of Health National Center for Research Resources Southeastern Pre-doctoral Training in Clinical Research [Grant 1T32 RR023258].
Parts of this study were presented in Master's thesis (Reeves O III. Ethanol Interactions with dl-Methylphenidate versus d-Methylphenidate in Humans. Charleston, Medical University of South Carolina, 2011) and presented in abstract form [Reeves O, Straughn A, Bell G, Bernstein H, Malcolm R, and Patrick K (2011) Ethanol elevates plasma dexmethylphenidate and dl-methylphenidate concentrations and potentiates subjective effects. J Clin Pharmacol 51:1332] at the 40th Annual Meeting of the American College of Clinical Pharmacology; 2011 Sept 10–12, 2011; Chicago, IL.
- Received August 23, 2012.
- Accepted October 25, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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