Ethylphenidate, being almost identical to methylphenidate in both structure and pharmacodynamics, likely also doesn't solely act as a "classical" reuptake inhibitor but primarily as aninverse agonist at thedopamine transporter (DAT), inducing dopaminetransporter reversal and subsequent dopamine release from theaxon terminal into the synaptic cleft in a manner similar to but distinct from amphetamines.[3]
Ethylphenidate metabolizes into methylphenidate andritalinic acid.[4]
Tiny amounts of ethylphenidate can be formedin vivo whenethanol andmethylphenidate are coingested, viahepatictransesterification.[5] Ethylphenidate formation appears to be more common when large quantities of methylphenidate andalcohol are consumed at the same time, such as in non-medical use oroverdose scenarios.[6] However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate.[7] Additionally, only a small percentage of the consumed methylphenidate is converted to ethylphenidate.[5]
Thiscarboxylesterase-dependent transesterification process is also known to occur whencocaine and alcohol are consumed together, formingcocaethylene.[8]
All available data on ethylphenidate's pharmacodynamics are drawn from studies conducted on rodents.[citation needed] Ethylphenidate is more selective to thedopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[7] but has significantly less activity on thenorepinephrine transporter (NET).[9] Itsdopaminergicpharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for itseuphoric and reinforcing effects.[10]
The following is ethylphenidate's binding profile in the mouse, alongside methylphenidate's. Figures for both theracemic and thedextrorotaryenantiomers are given:[9]
Ethylphenidate is illegal in theNetherlands, as theOpium Law List I covers it, as of April 27, 2018[12]
In the United States, effective November 21, 2024, Etheylphenidate was placed in Schedule I of theControlled Substances Act.[13]
On September 22, 2023, the DEA filed a proposed rule for placement of Ethylphenidate into Schedule I status. Public commenting opened on September 22, 2023, and closed on November 21, 2023.[11]
Ethylphenidate was made schedule I at the state level inAlabama on March 18th, 2014.[14]
Ethylphenidate is illegal in Sweden as of December 15, 2012.
Ethylphenidate is illegal to manufacture, distribute or import in the UK, as of 10 April 2015 it has been placed under aTemporary Class Drug Order which automatically places it in aClass-B-like category.[15] Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year from 26 June 2016.[16]
Ethylphenidate is illegal inJersey under the Misuse of Drugs (Jersey) Law 1978.[17]
Australian state and federal legislation contains provisions that mean that analogues of controlled drugs are also covered by the legislation. Ethylphenidate would be an analogue ofmethylphenidate under this legislation.[18]
^Heal DJ, Gosden J, Smith SL (December 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine".Neuropharmacology. CNS Stimulants.87:19–40.doi:10.1016/j.neuropharm.2014.06.012.PMID24953830.
^Negreira N, Erratico C, van Nuijs AL, Covaci A (January 2016). "Identification of in vitro metabolites of ethylphenidate by liquid chromatography coupled to quadrupole time-of-flight mass spectrometry".Journal of Pharmaceutical and Biomedical Analysis.117 (5):474–84.doi:10.1016/j.jpba.2015.09.029.hdl:10067/1301870151162165141.PMID26454340.
^abMarkowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (June 2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol".Drug Metabolism and Disposition.28 (6):620–4.PMID10820132.
^Markowitz JS, Logan BK, Diamond F, Patrick KS (August 1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion".Journal of Clinical Psychopharmacology.19 (4):362–6.doi:10.1097/00004714-199908000-00013.PMID10440465.
^abcPatrick KS, Williard RL, VanWert AL, Dowd JJ, Oatis JE, Middaugh LD (April 2005). "Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol".Journal of Medicinal Chemistry.48 (8):2876–81.doi:10.1021/jm0490989.PMID15828826.
^Bourland JA, Martin DK, Mayersohn M (December 1997). "Carboxylesterase-mediated transesterification of meperidine (Demerol) and methylphenidate (Ritalin) in the presence of [2H6]ethanol: preliminary in vitro findings using a rat liver preparation".Journal of Pharmaceutical Sciences.86 (12):1494–6.doi:10.1021/js970072x.PMID9423167.
^abWilliard RL, Middaugh LD, Zhu HJ, Patrick KS (February 2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity".Behavioural Pharmacology.18 (1):39–51.doi:10.1097/FBP.0b013e3280143226.PMID17218796.S2CID20232871.
^"Opiumwet" [Opium Act].Ministerie van Binnenlandse Zaken en Koninkrijksrelaties [Ministry of the Interior and Kingdom Relations] (in Dutch). Retrieved30 January 2022.
^Parks C, McKeown D, Torrance HJ (December 2015). "A review of ethylphenidate in deaths in east and west Scotland".Forensic Science International.257:203–208.doi:10.1016/j.forsciint.2015.08.008.PMID26375622.
^"关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Archived fromthe original on 1 October 2015. Retrieved1 October 2015.
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