Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity

Abstract

Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose-responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor. These experiments establish the feasibility of the B6 mouse model for examining the interactive effects of ethanol and methylphenidate. As reported for humans, concurrent exposure of B6 mice to methylphenidate and ethanol more readily formed l-ethylphenidate than d-ethylphenidate, and the l-isomers of both methylphenidate and ethylphenidate were biologically inactive. The observed reduced stimulatory effect of d-ethylphenidate relative to d-methylphenidate appears not to be the result of brain dispositional factors, but rather may be related to its reduced inhibition of the norepinephrine transporter, perhaps altering the interaction of dopaminergic and noradrenergic neural systems.

Analysis of six ‘neuro‐enhancing’ phenidate analogs

“…[21,22] It has also been long recognized that ethylphenidate is formed in vivo following co-administration of methylphenidate with alcohol. [25,26] The reaction of governments in the European Union to the challenge posed by NPS can be broadly differentiated into three legal response types. These may consist of a) the application of existing laws designed for consumer-or health-protection and pharmaceutical legislation;…”

Ritalin Use Modifies Alcohol Effects in Rats

“…In comparison to MPD, ethylphenidate blocks the norepinephrine transporter less potently [46]. These findings could indicate that there is an imbalance of the interactions which occur between the noradrenergic and the dopaminergic systems within the brain [46]. Methylphenidate administration alone increases locomotor activity.…”

“…Upon MPD/ethanol co-administration in mice, wholebrain concentrations of ethylphenidate were found to be higher in comparison to when methylphenidate was given alone. In comparison to MPD, ethylphenidate blocks the norepinephrine transporter less potently [46]. These findings could indicate that there is an imbalance of the interactions which occur between the noradrenergic and the dopaminergic systems within the brain [46].…”

“…The formation of the metabolite ethylphenidate has been shown to occur in response to the co-administration of ethanol and MPD [45]. The metabolite ethylphenidate given alone elicits increased locomotor activity in a dose response characteristic, albeit less intensely than methylphenidate [46]. Upon MPD/ethanol co-administration in mice, wholebrain concentrations of ethylphenidate were found to be higher in comparison to when methylphenidate was given alone.…”

Seven fatalities associated with ethylphenidate

“…The long term abuse potential is hard to determine without more detailed studies however the pharmacology of ethylphenidate suggests that there is a significant risk of abuse. Ethylphenidate exists as a racemic mixture with -(l) and + (d) isomers, pharmacological studies have shown that the individual isomers have different pharmacological activity [26,27]. In vitro studies on human monoamine transporters 5-HT (SERT), noradrenaline (NET) and dopamine (DAT) expressed in HEK293 cells evaluated the pharmacology of the racemic mixture (-/+) and the individual isomers have shown that, (+) ethylphenidate exhibited potent effects on DAT uptake inhibition (Ki -27 nM), (-/+) ethylphenidate was slightly less potent (Ki -95 nM) and (-) ethylphenidate was inactive (1730 nM).…”