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.

Keywords: absorption; bioavailability; dexmethylphenidate; drug interaction; ethanol; ethylphenidate; metabolism; methylphenidate; pharmacokinetics/pharmacodynamics; transesterification.

Figure 1

The absolute configuration of MPH enantiomers and the CES1-mediated enantioselective transesterification and hydrolysis to l-EPH and l-ritalinic acid, respectively.

Figure 2

(a) Mean d-MPH plasma concentrations (+/- S.D.) in 24 normal human subjects (12M/12W) after administering dl-MPH (0.3 mg/kg) alone (□) or dosing with dl-MPH (0.3 mg/kg) followed by ethanol (0.6 g/kg) 0.5 h later consumed over 0.25 h (■); (b) Mean d-MPH plasma concentrations after dosing with dexMPH (0.15 mg/kg) alone (Δ) or dosing with dexMPH (0.15 mg/kg) followed by ethanol (0.6 g/kg;) 0.5 h later consumed over 0.25 h (▲) (from with permission).

Figure 3

Mean l-MPH (◆) and l-EPH (■) plasma concentrations (+/- S.D.) in 24 normal human subjects administrated dl-MPH (0.3 mg/kg) followed by ethanol (0.6 g/kg) 0.5 h later consumed over 0.25 h. Mean l-MPH (◇) and l-EPH (□; not detectable) plasma concentrations in 24 normal human subjects following administration of dl-MPH (0.3 mg/kg) alone (from with permission).

Figure 4

Plasma concentration-time profile of dl-MPH and dl-EPH isomers from a healthy male volunteer administered 0.3 mg/kg dl-MPH with or without ethanol (0.6 g/kg; see Figure 1 legend for dosing details) using more recently developed, higher sensitivity technology capable of quantifying d-EPH (from with permission).