Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers. Issue 4 (August 2017)

• Record Type: Journal Article
• Authors: Zhu, Hao-Jie; Patrick, Kennerly S.; Straughn, Arthur B.; Reeves, Owen T.; Bernstein, Hilary; Shi, Jian; Johnson, Heather J.; Knight, Joshua M.; Smith, Aaron T.; Malcolm, Robert J.; Markowitz, John S.
• Is Part Of: Journal of clinical psychopharmacology. Volume 37:Issue 4(2017)
• Publication Date: 2017-08
• Subjects: biomarker -- carboxylesterase 1 -- dexmethylphenidate -- drug abuse -- drug interaction -- ethanol -- ethylphenidate -- humans -- methylphenidate -- pharmacodynamics -- pharmacokinetics -- spheroidal oral drug absorption system -- stimulant -- visual analog scale; Psychopharmacology -- Periodicals; Psychopharmacology -- Periodicals; Psychopharmacologie -- Périodiques; Psychopharmacology; Periodicals; 615.78
• DOI: 10.1097/JCP.0000000000000721
• Languages: English
• ISSNs: 0271-0749

Abstract

Abstract: Background/Purpose: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration ( C max ) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. Methods: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. Findings/Results: Ethanol increased the second pulse of d-MPH C max for dl-MPH by 35% ( P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% ( P < 0.05). The respective values for enantiopure d-MPH were 27% ( P = 0.001) and 20% ( P < 0.01). The carboxylesterase 1–mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. Implications/Conclusions: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder–alcohol use disorder.