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

  title={Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity},
  author={Robin L Williard and Lawrence D. Middaugh and Hao-Jie Zhu and Kennerly Sexton Patrick},
  journal={Behavioural Pharmacology},
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… 

In Vitro Neurochemical Assessment of Methylphenidate and Its “Legal High” Analogs 3,4-CTMP and Ethylphenidate in Rat Nucleus Accumbens and Bed Nucleus of the Stria Terminalis

All three psychostimulant drugs, through their effects on dopamine efflux, may have addictive liability although the effect of 3,4-CTMP on dopamine suggests that it might be most addictive and ethylphenidate least addictive.

Ethylphenidate as a selective dopaminergic agonist and methylphenidate-ethanol transesterification biomarker.

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

Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?

Data from in vitro, animal, and human studies support the premise that the d-enantiomer of MPH mediates the neurophysiological actions of MPH and therefore likely mediates its clinical efficacy.

Differential Influences of Ethanol on Early Exposure to Racemic Methylphenidate Compared with Dexmethylphenidate in Humans

The hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d- MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPh to l-EPH is tested.

Use of cognitive enhancers: methylphenidate and analogs.

Careful monitoring and systematic control of methylphenidate analogs should be undertaken to reduce the uprising threat, and education efforts should be made among high-risk populations.

Isopropylphenidate: an ester homolog of methylphenidate with sustained and selective dopaminergic activity and reduced drug interaction liability.

IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH.

Metabolomics of Methylphenidate and Ethylphenidate: Implications in Pharmacological and Toxicological Effects

  • R. Dinis-Oliveira
  • Biology, Chemistry
    European Journal of Drug Metabolism and Pharmacokinetics
  • 2016
It is expected that knowing the metabolomics of MPH may provide further insights regarding individual contribution for MPH pharmacodynamics and toxicological effects, namely if ethanol is co-consumed.

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice

The enhanced behavioral effects when EtOH is combined with MPH are likely due to the selective increase in brain d-MPH concentrations, and new clinical perspectives regarding enhanced ataxic effects of this drug combination are provided.

The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice



Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol.

In view of the known dopaminergic activity of racemic ethylphenidate, it remains possible that under certain circumstances of higher level dosing, e.g., in the abuse of methylphenidate and ethanol, the metabolite ethyl phenidate may contribute to drug effects.

Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol.

Ethanol elevates methylphenidate plasma concentrations and yields the metabolite ethylphenidate, and binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine.

Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning

The more active enantiomer, as predicted, was d-methylphenidate, but the l-enantiomer interfered with its effects, suggesting that clinical potency of d- methylphenidate may be more than twice that of the racemate.

Effects of Methylphenidate on Extracellular Dopamine, Serotonin, and Norepinephrine: Comparison with Amphetamine

The hypothesis that a stimulant‐induced increase in serotonin is necessary for the appearance of stereotyped behaviors is not supported, as methylphenidate promotes a dose‐dependent behavioral profile that is very comparable to that of amphetamine.

Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion.

The first detection of ethylphenidate in human blood and liver samples obtained from two suicide victims who had overdosed on methylphenidate and coingested ethanol is described.

Pharmacology of the enantiomers of threo-methylphenidate.

Results suggest that synaptic inhibition of catecholaminergic uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

Influence of Ethanol and Gender on Methylphenidate Pharmacokinetics and Pharmacodynamics

Women reported a significantly greater stimulant effect than men when questioned “Do you feel any drug effect?” (P<0.05), in spite of lower mean plasma d‐MPH area under the response–time curves in women.

Methylphenidate and brain dopamine neurotoxicity