title: Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.
abstract: We review the pharmaceutical science of ethylphenidate (EPH) in the contexts of drug discovery, drug interactions, biomarker for dl-methylphenidate (MPH)-ethanol exposure, potentiation of dl-MPH abuse liability, contemporary "designer drug," pertinence to the newer transdermal and chiral switch MPH formulations, as well as problematic internal standard. d-EPH selectively targets the dopamine transporter, whereas d-MPH exhibits equipotent actions at dopamine and norepinephrine transporters. This selectivity carries implications for the advancement of tailored attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in the era of genome-based diagnostics. Abuse of dl-MPH often involves ethanol coabuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by significantly increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided using dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria occurs following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: an otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; a substimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; ethanol elevates blood, brain, and urinary d-MPH concentrations while forming l-EPH. Integration of EPH preclinical neuropharmacology with clinical studies of MPH-ethanol interactions provides a translational approach toward advancement of ADHD personalized medicine and management of comorbid alcohol use disorder.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425-1400. Electronic address: patrickk@musc.edu.
authors.forename: Kennerly S
authors.initials: KS
authors.lastname: Patrick
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425-1400.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Corbin
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425-1400.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Murphy
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004951:Esterification / Q000502:physiology; D000431:Ethanol / Q000378:metabolism; D006801:Humans; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D018491:Dopamine Agonists; D008774:Methylphenidate; D000431:Ethanol; C042400:ethylphenidate; D004298:Dopamine
keywords: absorption; bioavailability; dexmethylphenidate; drug interaction; ethanol; ethylphenidate; metabolism; methylphenidate; pharmacokinetics/pharmacodynamics; transesterification