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Ethylphenidate
Systematic (IUPAC) name
ethyl 2-phenyl-2-piperidin-2-ylacetate
Identifiers
CAS number 57413-43-1
ATC code none
PubChem 3080846
Chemical data
Formula C 15H21NO2  
Mol. mass 247.33274 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Variable
Protein binding Unknown
Metabolism Hepatic transesterification of prodrugs methylphenidate and ethanol
Half life Dependent on methylphenidate administration.[1]
Excretion Urine
Therapeutic considerations
Pregnancy cat.  ?
Legal status Presumably Controlled in the US
Routes N/A

Ethylphenidate (EP) is a potent psychostimulant that acts as both a dopamine reuptake inhibitor and norepinephrine 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.

It is most commonly formed when ethanol and methylphenidate are coingested, via hepatic transesterification.[1] 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.[2] This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.[3]

Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[4] but has significantly less activity on the norepinephrine transporter (NET).[5] It has nearly an identical dopaminergic pharmacodynamic profile as methylphenidate, possessing appreciable affinity for the inhibitory G protein-coupled dopamine subtype-2 receptors in the striatum and mesolimbic regions of the brain,[6] including the nucleus accumbens,[7] which is primarily responsible for its euphoric and reinforcing effects.[8]

Interestingly, the eudysmic ratio for ethylphenidate is superior to that seen for TMP.[4]

Compound[5] Binding DAT Binding NET Uptake DA Uptake NE
d-TMP 139 408 28 46
d-TEP 276 2479 24 247
dl-TMP 105 1560 24 31
dl-TEP 382 4824 82 408

TEP is less stimulatory than TMP at 5mg/kg, although both compounds generalize at 10mg/kg. This is suggestive of a noradrenergic stimulatory effect present for TMP at lower doses.

Metabolism of dl-TMP coingested with ethanol

The fate of racemic-TMP does to some extent depend on whether it is subjected to first pass metabolism or not.

Clearly, the transesterase enzymes responsible for converting TMP → TEP are enantioselective, as are the hydrolytic enzymes that metabolize TMP → ritalinic acid.

The para-hydroxy metabolite of l-TMP is important since this accumulates in the brain, whereas l-ritalinic acid does not.

Depending on the study chosen, rac-TMP is 75% the strength of d-TMP. If levo-TMP were completely inactive it would be expected that rac-TMP should only be 50% the strength of dextro-TMP.

Racemic-TMP is enantioselectively converted, only the inactive isomer, l-TMP forms appreciable amounts of ethylphenidate when it is coingested with ethanol, whereas the biologically active eutomer d-TMP does not react with ethanol to any significant extent.

References

  1. ^ a b Markowitz, JS; Devane; Boulton; Nahas; Risch; Diamond; Patrick (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug metabolism and disposition: the biological fate of chemicals 28 (6): 620–4. PMID 10820132.   edit
  2. ^ Markowitz, JS; Logan; Diamond; Patrick (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.   edit
  3. ^ Bourland, J.; Martin, D.; Mayersohn, M. (1997). "Carboxylesterase-mediated transesterification of meperidine (Demerol) and methylphenidate (Ritalin) in the presence of 2H6ethanol: preliminary in vitro findings using a rat liver preparation". Journal of pharmaceutical sciences 86 (12): 1494–1496. doi:10.1021/js970072x. PMID 9423167.   edit
  4. ^ a b Patrick, K.; Williard, R.; Vanwert, A.; Dowd, J.; Oatis Je, J.; Middaugh, L. (2005). "Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol". Journal of medicinal chemistry 48 (8): 2876–2881. doi:10.1021/jm0490989. PMID 15828826.   edit
  5. ^ a b Williard, R.; Middaugh, L.; Zhu, H.; Patrick, K. (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.   edit
  6. ^ Schweri, MM; Skolnick; Rafferty; Rice; Janowsky; Paul (1985). "3HThreo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters". Journal of neurochemistry 45 (4): 1062–70. doi:10.1111/j.1471-4159.1985.tb05524.x. PMID 4031878.   edit
  7. ^ Volkow, ND; Ding; Fowler; Wang; Logan; Gatley; Dewey; Ashby et al. (1995). "Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain". Archives of general psychiatry 52 (6): 456–63. PMID 7771915.   edit
  8. ^ Jatlow, P; Elsworth; Bradberry; Winger; Taylor; Russell; Roth (1991). "Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion". Life sciences 48 (18): 1787–94. doi:10.1016/0024-3205(91)90217-Y. PMID 2020260.   edit

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