Date of Award

1-1-2012

Embargo Period

11-20-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

College

College of Graduate Studies

First Advisor

Kennerly Patrick

Second Advisor

Roger White

Third Advisor

Sherine Chan

Fourth Advisor

Daniel Lackland

Abstract

Adult Attention-Deficit/Hyperactivity Disorder (ADHD) affects~ 4.4% of the adult population, and patients with this disorder frequently have comorbid substance abuse disorders. Methylphenidate (MPH) is considered a first line pharmacotherapy agent in the treatment of ADHD, and is commonly used or co-abused with alcohol. Hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive 1-MPH isomer to only 1-2%. Co-administration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations, as well as CES1 mediated enantioselective transesterification of 1-MPH to 1-ethylphenidate (EPH). The present study tested the hypothesis that administering the pure isomer dexmethylphenidate (d­l-MPH) will reduce the effect of ethanol on d-MPH bioavailability by eliminating metabolic competition from pre-systemic CESI transesterification of 1-MPH, "sparing" d-MPH. 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) in a randomized 4x4 crossover study. Plasma samples were analyzed for pharmacokinetic parameters and subjective effects were reported utilizing visual analog scales (VAS) to assess abuse potential. During the absorption phase of dl-MPH (AUC0.5-2), ethanol elevated plasma d-MPH concentrations by approximately 56% (p<0.001), as well as increased positive subjective effects as reported by VAS. These findings are consistent with I-MPH inhibiting first-pass metabolic clearance of d-MPH, as AUC0.5-2 of d-MPH was not significantly influenced when ethanol was concomitantly administered with enantiopure d-MPH. More rapid d-MPH absorption has correlated with increased abuse liability, however, ethanol did increased-MPH AUCinf and Cmax with concomitant administration of either dl-MPH (p<0.001) or d-MPH (p<0.001), suggesting enantiopure d-MPH formulations may not completely avoid pharmacokinetic/pharmacodynamic MPH-ethanol interactions and appropriate pharmacologic alternatives to MPH should be considered when treating adult ADHD with comorbid substance abuse disorder

Rights

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