JC PGC. Contributed reagents/materials/ analysis tools: CGMG SAJ JC PGC.JC PGC. Contributed reagents/materials/ analysis tools:

JC PGC. Contributed reagents/materials/ analysis tools: CGMG SAJ JC PGC.
JC PGC. Contributed reagents/materials/ analysis tools: CGMG SAJ JC PGC. Wrote the manuscript: CGMG JC.
NIH Public AccessAuthor ManuscriptJ Pharm Sci. Author manuscript; offered in PMC 2014 December 01.Published in final edited kind as: J Pharm Sci. 2014 December ; 103(12): 3834842. doi:10.1002/jps.24202.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptEthylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarkerKennerly S. Patrick, Timothy R. Corbin, and Cristina E. Murphy Division of Drug Discovery and Biomedical Sciences, Medical University of South 5-HT7 Receptor Antagonist Purity & Documentation Carolina, 280 Calhoun St., PO Box 250140, Charleston, SC 29425-1400, USAAbstractWe critique the pharmaceutical science of ethylphenidate (EPH) inside the contexts of drug discovery; drug interactions; biomarker for dl-methylphenidate (MPH)-ethanol exposure; potentiation of dlMPH abuse liability; contemporary “designer drug”; pertinence towards the newer transdermal and chiral switch MPH formulations; too as problematic internal normal. d-EPH selectively targets the dopamine transporter even though 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 frequently entails ethanol co-abuse. Carboxylesterase 1 enantioselectively transesterifies l-MPH with ethanol to yield l-EPH accompanied by drastically increased early exposure to d-MPH and rapid potentiation of euphoria. The pharmacokinetic component of this drug interaction can largely be avoided employing dexmethylphenidate (dexMPH). This notwithstanding, maximal potentiated euphoria happens following dexMPH-ethanol. C57BL/6 mice model dl-MPH-ethanol interactions: An otherwise depressive dose of ethanol synergistically increases dl-MPH stimulation; A sub-stimulatory dose of dl-MPH potentiates a low, stimulatory dose of ethanol; Ethanol elevates blood, brain and urinary d-MPH concentrations although forming lEPH. Integration of EPH preclinical neuropharmacology with clinical research of MPH-ethanol interactions provides a translational PKCι Biological Activity approach toward advancement of ADHD customized medicine and management of comorbid alcohol use disorder.Key phrases ethylphenidate; methylphenidate; ethanol; dexmethylphenidate; transesterification; drug interaction; pharmacokinetics/pharmacodynamics; metabolism; absorption; bioavailabilityIntroduction: Methylphenidate-ethanol misuse and co-abuseThe quantity of attention-deficit/hyperactivity disorder (ADHD) diagnoses has continued to raise in recent years.1 The stimulant dl-methylphenidate (MPH) has lengthy remained theCorrespondence to: Kennerly S. Patrick, Ph.D. patrickk@musc.edu, Telephone 843-792-8429; Fax 843-792-2620. K.S. Patrick serves as a consultant for Noven, Alza, UCB and Shire and Ortho-Janssen. He has served as a consultant to Johnson Johnson and Celgene inside the last five years and has had a provisional patent for isopropylphenidate (ritalinic acid isopropyl ester) as a novel psychotropic agent via the MUSC Foundation for Research Improvement, with a Notice of abandonment Jan 2014. No other activities of the authors could possibly be construed as conflicts.Patrick et al.Pagemost widely prescribed drug to treat ADHD. In adolescents, MPH prescriptions exceed these for all other drugs regardless of therapeutic class.2 Also, alcohol abus.