Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

Abstract

Background/purpose: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) 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 Cmax 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.

FIGURE 1

(Top): Arithmetic mean (+/− SD) d-MPH plasma concentrations after dosing with MR-dl-MPH (40 mg) alone (□) or dosing with racemic MR-dl-MPH (40 mg MR) followed by ethanol (0.6 g/kg) 4–4.25 h later (▪); (Bottom): Arithmetic mean d-MPH plasma concentrations after dosing with enantiopure MR-d-MPH (20 mg) alone (Δ) or dosing with MR-d-MPH (20 mg) followed by ethanol (0.6 g/kg;) 4–4.25 h later. Values only include those at or above the lower limit of detection (≥ 0.025 ng/ml).

FIGURE 2

Visual analog subscale positive subjective drug effects of “Stimulated; “High”; “Good”; and “Any effect” (0 – 12.5 hours): Racemic MR-dl-MPH (40 mg) was administered alone (□) or followed by ethanol (0.6 g/kg) 4–4.25 hours later (▪). Enantiopure MR-d-MPH (20 mg) was administered alone (Δ) or followed by ethanol (0.6 g/kg) 4–4.25 hours later (■). MPH administration was at T = 0 hours. Effect ratings were from 0 = “Not at all” to 100 = “Extremely”; Values represent the arithmetic mean (+/− SD); *P < 0.05; **P < 0.01; ^aP = 0.071; ^bP = 0.078.