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Ethylphenidate

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Ethylphenidate
Clinical data
Routes of
administration		By mouth, insufflation, inhalation, sublingual, rectal, intramuscular, intravenous
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
BioavailabilityVariable
Protein bindingUnknown
MetabolismHepatic transesterification of prodrugs methylphenidate and ethanol
ExcretionUrine, sweat
Identifiers
  • (RS)-Ethyl 2-phenyl-2-piperidin-2-ylacetate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC15H21NO2
Molar mass247.338 g·mol−1
3D model (JSmol)
  • CCOC(=O)C(C1CCCCN1)C2=CC=CC=C2
  • InChI=1S/C15H21NO2/c1-2-18-15(17)14(12-8-4-3-5-9-12)13-10-6-7-11-16-13/h3-5,8-9,13-14,16H,2,6-7,10-11H2,1H3 checkY
  • Key:AIVSIRYZIBXTMM-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ethylphenidate (EPH) is a central nervous system (CNS) stimulant and a close analog of methylphenidate.

Ethylphenidate acts as a norepinephrine–dopamine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.

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 an inverse agonist at the dopamine transporter (DAT), inducing dopamine transporter reversal and subsequent dopamine release from the axon terminal into the synaptic cleft in a manner similar to but distinct from amphetamines.[3]

Pharmacology

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Pharmacokinetics

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Ethylphenidate metabolizes into methylphenidate and ritalinic acid.[4]

Tiny amounts of ethylphenidate can be formed in vivo when ethanol and methylphenidate are coingested, via hepatic transesterification.[5] Ethylphenidate formation appears to be more common when large quantities of methylphenidate and alcohol are consumed at the same time, such as in non-medical use or overdose 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]

This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.[8]

Pharmacodynamics

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All available data on ethylphenidate's pharmacodynamics are drawn from studies conducted on rodents.[citation needed] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[7] but has significantly less activity on the norepinephrine transporter (NET).[9] Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.[10]

The eudysmic ratio for ethylphenidate is superior to that of methylphenidate.[7][failed verification]

The following is ethylphenidate's binding profile in the mouse, alongside methylphenidate's. Figures for both the racemic and the dextrorotary enantiomers are given:[9]

Compound Binding DAT

Ki (nM)

Binding NET

Ki (nM)

Uptake DA

IC50 (nM)

Uptake NE

IC50 (nM)

d-methylphenidate 139 408 28 46
d-ethylphenidate 276 2479 24 247
dl-methylphenidate 105 1560 24 31
dl-ethylphenidate 382 4824 82 408

Legality

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  • Ethylphenidate is a schedule II drug under the Convention on Psychotropic Substances.[11]
  • Ethylphenidate is illegal in the Netherlands, as the Opium Law Lijst I covers it, as of April 27, 2018 [12]
  • Ethylphenidate is not explicitly controlled in the US as part of the Controlled Substances Act but it could possibly be considered an analog of a Schedule II substance (methylphenidate) under the Federal Analog Act if sold for human consumption.
    • In the United States, 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 in Alabama on March 18th, 2014.[13]
  • 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 a Temporary Class Drug Order which automatically places it in a Class-B-like category.[14] 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.[15]
  • Ethylphenidate is illegal in Jersey under the Misuse of Drugs (Jersey) Law 1978.[16]
  • 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 of methylphenidate under this legislation.[17]
  • Ethylphenidate is controlled in Canada under the Controlled Drugs and Substances Act under Schedule III as of May 5, 2017.[18]
  • Ethylphenidate is illegal in Germany as of May 7, 2013.[19]
  • Ethylphenidate is illegal in Austria by the "Neue Psychoaktive Substanzen Gesetz" (New Psychoactive Substances Act) NPSG since 1 January 2012
  • Ethylphenidate is illegal in Denmark as of February 1, 2013.[20]
  • Ethylphenidate is illegal in Poland by "the Act on Counteracting Drug Addiction" since July 1, 2015.[21]
  • It is illegal in Lithuania to use, buy, possess, transport, sell or import Ethylphenidate from 2015 [22]
  • As of October 2015, ethylphenidate is a controlled substance in China.[23]
  • In Finland ethylphenidate is scheduled in government decree on substances, preparations and plants considered to be narcotic drugs.[24]

See also

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References

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  1. ^ Anvisa (2023-07-24). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-07-25). Archived from the original on 2023-08-27. Retrieved 2023-08-27.
  2. ^ "Substance Details Ethylphenidate". Retrieved 2024-01-22.
  3. ^ 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. PMID 24953830.
  4. ^ 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. PMID 26454340.
  5. ^ a b Markowitz 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. PMID 10820132.
  6. ^ 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. PMID 10440465.
  7. ^ a b c Patrick 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. PMID 15828826.
  8. ^ 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. PMID 9423167.
  9. ^ a b Williard 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. PMID 17218796. S2CID 20232871.
  10. ^ Jatlow P, Elsworth JD, Bradberry CW, Winger G, Taylor JR, Russell R, Roth RH (1991). "Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion" (PDF). Life Sciences. 48 (18): 1787–94. doi:10.1016/0024-3205(91)90217-Y. hdl:2027.42/29671. PMID 2020260.
  11. ^ a b "Schedules of Controlled Substances: Placement of Ethylphenidate in Schedule I" (PDF). Federal Register. 88 (183): 65,332. 22 September 2023. Retrieved 16 October 2023.
  12. ^ "Opiumwet" [Opium Act]. Ministerie van Binnenlandse Zaken en Koninkrijksrelaties [Ministry of the Interior and Kingdom Relations] (in Dutch). Retrieved 30 January 2022.
  13. ^ https://www.alabamapublichealth.gov/blog/assets/controlledsubstanceslist.pdf [bare URL PDF]
  14. ^ "'Legal highs' to be banned under temporary power". Gov.uk.
  15. ^ "Re: TCDOs and ACMD position on methylphenidate-based NPS" (PDF). Gov.uk. 2016-02-29. Retrieved 2016-11-28.
  16. ^ "Misuse of Drug (General Provisions) (Jersey) Order 2009". Jersey Legal Information Board. January 2014. Retrieved 2023-09-28.
  17. ^ 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. PMID 26375622.
  18. ^ "Order Amending Schedule III to the Controlled Drugs and Substances Act (Methylphenidate)". Canada Gazette. Government of Canada, Public Works and Government Services Canada, Public Services and Procurement Canada, Integrated Services Branch, Canada. 2017-04-05.
  19. ^ "BTMG - Einzelnorm". Archived from the original on 2013-10-16. Retrieved 2014-02-08.
  20. ^ "Retsinformation". Retsinformation.dk. Retrieved 30 January 2022.
  21. ^ "Ustawa z dnia 24 kwietnia 2015 r. o zmianie ustawy o przeciwdziałaniu narkomanii oraz niektórych innych ustaw". Isap.sejm.gov.pl.
  22. ^ "Vartotojui - tik saugūs ir efektyvūs vaistai! - I SĄRAŠAS". Vvkt.lt.
  23. ^ "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 from the original on 1 October 2015. Retrieved 1 October 2015.
  24. ^ "FINLEX ® - Etusivu". www.finlex.fi.
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