Date of Award

2011

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

College of Graduate Studies

First Advisor

Kennerly S. Patrick

Second Advisor

Yuri Peterson

Third Advisor

Sherine Chan

Fourth Advisor

Lindsay DeVane

Fifth Advisor

John Woodward

Sixth Advisor

James M. Chapman

Abstract

The persistence of attention-deficit/hyperactivity disorder (ADHO) into adulthood has been increasingly recognized over the past few decades and the stimulant drug dl-methylphenidate (MPH) has remained a first-line pharmacotherapeutic agent in the treatment of ADHD. Many adult ADHD patients who are prescribed MPH report concomitant use with ethanol. In humans, coadministration of dl-MPH and ethanol results in pharmacokinetic and pharmacodynamic drug - drug interactions. Ethanol elevates biological concentrations of the pharmacologically active d-MPH isomer and yields the metabolic transesterification product ethylphenidate (EPH). EPH appears to be formed through the actions of carboxylesterase 1 (CES1) which exhibits I-MPH substrate enantioselectivity in both the metabolic transesterification and deesterification pathways. Accordingly, the mean absolute oral bioavailability of I-MPH is limited to only 1-3% compared to approximately 30% for d-MPH. However, dosing with transdermal dl-MPH (Daytrana® avoids the extensive oral presystemic metabolism and leads to approximately 50 times more I-MPH reaching the systemic circulation when compared with oral dosing. Studies using human subjects are limited in their ability to examine abuse like doses. Using a C57BL/6J mouse model, the experiments in this dissertation were designed to: 1) Establish the rewarding properties and abuse potential of Lv. dl-MPH as evidenced by drug seeking behavior; 2) Investigate the pharmacokinetic interactions of dl-MPH and ethanol coabuse, placing an emphasis on the MPH transdermal system; 3) Investigate the pharmacodynamic interactions of dl-MPH and ethanol coabuse. The reward value of methylphenidate is evidenced by robust drug-seeking behavior in C57 mice, which are an appropriate model to investigate methylphenidate abuse liability. Pharmacokinetic studies showed that, as in humans, transdermal dl-MPH greatly facilitated the absorption of I-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of I-EPH and to an elevation in d-MPH concentrations with both transdermal and oral dl-MPH. While only guarded comparisons between transdermal and oral dl-MPH can be made due to route-dependent drug absorption rate differences, transdermal dl-MPH was associated with significant MPH - ethanol interactions. Pharmacodynamic studies showed that an otherwise depressive dose of ethanol significantly potentiated oral dl-MPH induced increases in total distance traveled for the first 100 min. Further, transdermal dl-MPH increased total distance traveled after a latency of 80 min, though this effect was not potentiated by concomitant ethanol. The results from these studies in combination with human data, provide a scientific basis for extending abuse precautions for the ethanol - dl-MPH combination in general, with a novel focus on transdermal dl-MPH.

Rights

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