Identification

Name
Dexmethylphenidate
Accession Number
DB06701
Type
Small Molecule
Groups
Approved, Investigational
Description

Dexmethylphenidate is the dextrorotary form of methylphenidate. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and thus a psychostimulant. It is used for treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Structure
Thumb
Synonyms
  • d-threo-methylphenidate
  • D-TMP
  • Dexmethylphenidate
Product Ingredients
IngredientUNIICASInChI Key
Dexmethylphenidate hydrochloride1678OK0E0819262-68-1JUMYIBMBTDDLNG-OJERSXHUSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FocalinTablet2.5 mg/1OralNovartis2001-11-30Not applicableUs
FocalinTablet10 mg/1OralNovartis2001-11-30Not applicableUs
FocalinTablet5 mg/1OralNovartis2001-11-30Not applicableUs
Focalin XRCapsule, extended release15 mg/1OralStat Rx USA2005-05-31Not applicableUs
Focalin XRCapsule, extended release10 mg/1OralNovartis2005-05-31Not applicableUs
Focalin XRCapsule, extended release40 mg/1OralNovartis2005-05-31Not applicableUs
Focalin XRCapsule, extended release30 mg/1OralNovartis2005-05-31Not applicableUs
Focalin XRCapsule, extended release5 mg/1OralNovartis2005-05-31Not applicableUs
Focalin XRCapsule, extended release35 mg/1OralNovartis2005-05-31Not applicableUs
Focalin XRCapsule, extended release20 mg/1OralNovartis2005-05-31Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dexmethylphenidate hydrochlorideTablet5 mg/1OralSun Pharmaceutical Industries, Inc.2013-09-26Not applicableUs
Dexmethylphenidate hydrochlorideCapsule, extended release30 mg/1OralImpax Generics2014-02-24Not applicableUs
Dexmethylphenidate HydrochlorideCapsule, extended release40 mg/1OralTeva2013-11-21Not applicableUs00093 5562 01 nlmimage10 b241d90e
Dexmethylphenidate HydrochlorideCapsule, extended release5 mg/1OralAvera McKennan Hospital2015-03-06Not applicableUs69189 555020180907 15195 n2m1g7
Dexmethylphenidate HydrochlorideCapsule, extended release5 mg/1OralActavis Pharma Company2015-08-062017-10-28Us
Dexmethylphenidate HydrochlorideTablet10 mg/1OralLupin Pharmaceuticals2015-12-04Not applicableUs
Dexmethylphenidate HydrochlorideTablet5 mg/1OralTeva Pharmaceuticals USA, Inc.2007-06-08Not applicableUs00093 5276 01 nlmimage10 f141f88f
Dexmethylphenidate HydrochlorideTablet5 mg/1OralKvk Tech,Inc2015-12-04Not applicableUs
Dexmethylphenidate HydrochlorideCapsule, extended release25 mg/1OralTeva2017-07-05Not applicableUs
Dexmethylphenidate HydrochlorideTablet2.5 mg/1OralSandoz2015-04-27Not applicableUs
International/Other Brands
Attenade (Celgene)
Categories
UNII
M32RH9MFGP
CAS number
40431-64-9
Weight
Average: 233.3062
Monoisotopic: 233.141578857
Chemical Formula
C14H19NO2
InChI Key
DUGOZIWVEXMGBE-CHWSQXEVSA-N
InChI
InChI=1S/C14H19NO2/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3/t12-,13-/m1/s1
IUPAC Name
methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate
SMILES
COC(=O)[C@@H]([C@H]1CCCCN1)C1=CC=CC=C1

Pharmacology

Indication

Dexmethylphenidate is used as a treatment for ADHD, ideally in conjunction with psychological, educational, behavioral or other forms of treatment.

Associated Conditions
Pharmacodynamics

Methylphenidate is a central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in children and for narcolepsy.

Mechanism of action

Methylphenidate blocks dopamine uptake in central adrenergic neurons by blocking dopamine transport or carrier proteins. Methylphenidate acts at the brain stem arousal system and the cerebral cortex and causes increased sympathomimetic activity in the central nervous system. Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.

TargetActionsOrganism
ASodium-dependent dopamine transporter
inhibitor
Human
ASodium-dependent noradrenaline transporter
inhibitor
Human
USodium-dependent serotonin transporter
inhibitor
Human
Absorption

11-52%

Volume of distribution
Not Available
Protein binding

30%

Metabolism

epatic, methylphenidate is metabolized primarily by de-esterification to ritalinic acid (α-phenyl-2-piperidine acetic acid, PPAA), which has little to no pharmacologic activity.

Route of elimination

Renal

Half life

2-4 hours

Clearance
Not Available
Toxicity

Insomnia, dizziness, nausea, stomach pain, euphoria, headache, anxiety, anorexia, and weight loss are common side effects. Symptoms of overdose include vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. LD50=190mg/kg (orally in mice)

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Dexmethylphenidate.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Dexmethylphenidate.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Dexmethylphenidate.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Dexmethylphenidate is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when 3,4-Methylenedioxyamphetamine is combined with Dexmethylphenidate.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Dexmethylphenidate.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dexmethylphenidate.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Dexmethylphenidate is combined with 5-methoxy-N,N-dimethyltryptamine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of serotonin syndrome can be increased when Dexmethylphenidate is combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Dexmethylphenidate.
Food Interactions
  • Avoid alcohol
  • Avoid excessive quantities of coffee or tea (caffeine)
  • Take on empty stomach: 1 hour before or 2 hours after meals

References

Synthesis Reference

Arie Gutman, "Process for the preparation of dexmethylphenidate hydrochloride." U.S. Patent US20040180928, issued September 16, 2004.

US20040180928
General References
Not Available
External Links
Human Metabolome Database
HMDB0015647
PubChem Compound
154101
PubChem Substance
99443255
ChemSpider
135807
BindingDB
50062915
ChEBI
51860
ChEMBL
CHEMBL827
PharmGKB
PA10054
Wikipedia
Dexmethylphenidate
ATC Codes
N06BA11 — Dexmethylphenidate

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedBasic ScienceHealthy Volunteers / Moods Disorders / Substance-Related Disorders1
1CompletedNot AvailableHealthy Volunteers2
1, 2CompletedBasic ScienceDrug Binding to DAT Receptors1
2Active Not RecruitingTreatmentAttention Deficit Disorder With Hyperactivity (ADHD) / Deficient Emotional Self-Regulation (DESR)1
2CompletedTreatmentNeoplasms / Tiredness1
3CompletedPreventionAttention Deficit Disorder With Hyperactivity (ADHD)1
3CompletedTreatmentAttention Deficit Disorder With Hyperactivity (ADHD)1
4CompletedTreatmentAttention Deficit Disorder With Hyperactivity1
4CompletedTreatmentAttention Deficit Disorder With Hyperactivity (ADHD)2
4CompletedTreatmentAttention Deficit Disorder With Hyperactivity (ADHD) / Deficient Emotional Self-Regulation (DESR)1
4CompletedTreatmentSarcoidosis1
Not AvailableNot Yet RecruitingNot AvailableAttention Deficit Disorder With Hyperactivity (ADHD) / Problem Behavior1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, extended releaseOral25 mg/1
Capsule, extended releaseOral35 mg/1
TabletOral10 mg/1
TabletOral2.5 mg/1
TabletOral5 mg/1
Capsule, extended releaseOral15 mg/1
Capsule, extended releaseOral30 mg/1
Capsule, extended releaseOral40 mg/1
Capsule, extended releaseOral10 mg/1
Capsule, extended releaseOral20 mg/1
Capsule, extended releaseOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5908850No1995-12-042015-12-04Us
US6355656No1995-12-042015-12-04Us
US6528530No1995-12-042015-12-04Us
US6228398No1999-11-012019-11-01Us
US6635284No1995-12-042015-12-04Us
US7431944No1995-12-042015-12-04Us
US5837284No1995-12-042015-12-04Us
US6730325No1999-11-012019-11-01Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.182 mg/mLALOGPS
logP1.47ALOGPS
logP2.25ChemAxon
logS-3.1ALOGPS
pKa (Strongest Basic)9.09ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.33 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity66.73 m3·mol-1ChemAxon
Polarizability26.23 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9941
Blood Brain Barrier+0.9663
Caco-2 permeable+0.6564
P-glycoprotein substrateSubstrate0.5466
P-glycoprotein inhibitor INon-inhibitor0.7964
P-glycoprotein inhibitor IINon-inhibitor0.9601
Renal organic cation transporterInhibitor0.532
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.5985
CYP450 1A2 substrateNon-inhibitor0.592
CYP450 2C9 inhibitorNon-inhibitor0.897
CYP450 2D6 inhibitorNon-inhibitor0.5245
CYP450 2C19 inhibitorNon-inhibitor0.9265
CYP450 3A4 inhibitorNon-inhibitor0.8539
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9328
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9648
BiodegradationNot ready biodegradable0.5759
Rat acute toxicity2.7718 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8466
hERG inhibition (predictor II)Non-inhibitor0.7491
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aralkylamines. These are alkylamines in which the alkyl group is substituted at one carbon atom by an aromatic hydrocarbyl group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Aralkylamines
Alternative Parents
Piperidines / Benzene and substituted derivatives / Methyl esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
show 1 more
Substituents
Aralkylamine / Monocyclic benzene moiety / Piperidine / Benzenoid / Methyl ester / Amino acid or derivatives / Carboxylic acid ester / Carboxylic acid derivative / Secondary aliphatic amine / Monocarboxylic acid or derivatives
show 10 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
methyl phenyl(piperidin-2-yl)acetate (CHEBI:51860)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Markowitz JS, Patrick KS: Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J Clin Psychopharmacol. 2008 Jun;28(3 Suppl 2):S54-61. doi: 10.1097/JCP.0b013e3181733560. [PubMed:18480678]
  2. Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, Gatley SJ, Pappas N: Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology (Berl). 1997 May;131(1):71-8. [PubMed:9181638]
  3. Davids E, Zhang K, Tarazi FI, Baldessarini RJ: Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology (Berl). 2002 Feb;160(1):92-8. Epub 2001 Dec 18. [PubMed:11862378]
  4. Volkow ND, Fowler JS, Gatley SJ, Dewey SL, Wang GJ, Logan J, Ding YS, Franceschi D, Gifford A, Morgan A, Pappas N, King P: Comparable changes in synaptic dopamine induced by methylphenidate and by cocaine in the baboon brain. Synapse. 1999 Jan;31(1):59-66. [PubMed:10025684]
  5. Wayment HK, Deutsch H, Schweri MM, Schenk JO: Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? J Neurochem. 1999 Mar;72(3):1266-74. [PubMed:10037500]
  6. Dresel SH, Kung MP, Huang X, Plossl K, Hou C, Shiue CY, Karp J, Kung HF: In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates. Eur J Nucl Med. 1999 Apr;26(4):342-7. [PubMed:10199939]
  7. Volkow ND, Wang GJ, Fowler JS, Fischman M, Foltin R, Abumrad NN, Gatley SJ, Logan J, Wong C, Gifford A, Ding YS, Hitzemann R, Pappas N: Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain. Life Sci. 1999;65(1):PL7-12. [PubMed:10403500]
  8. Izenwasser S, Coy AE, Ladenheim B, Loeloff RJ, Cadet JL, French D: Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Eur J Pharmacol. 1999 Jun 4;373(2-3):187-93. [PubMed:10414438]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  10. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  11. Viggiano D, Vallone D, Sadile A: Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling. Neural Plast. 2004;11(1-2):97-114. [PubMed:15303308]
  12. Tilley MR, Gu HH: The effects of methylphenidate on knockin mice with a methylphenidate-resistant dopamine transporter. J Pharmacol Exp Ther. 2008 Nov;327(2):554-60. doi: 10.1124/jpet.108.141713. Epub 2008 Aug 12. [PubMed:18698001]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Markowitz JS, Patrick KS: Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? J Clin Psychopharmacol. 2008 Jun;28(3 Suppl 2):S54-61. doi: 10.1097/JCP.0b013e3181733560. [PubMed:18480678]
  2. Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, Gatley SJ, Pappas N: Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology (Berl). 1997 May;131(1):71-8. [PubMed:9181638]
  3. Davids E, Zhang K, Tarazi FI, Baldessarini RJ: Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology (Berl). 2002 Feb;160(1):92-8. Epub 2001 Dec 18. [PubMed:11862378]
  4. Yang L, Wang YF, Li J, Faraone SV: Association of norepinephrine transporter gene with methylphenidate response. J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1154-8. [PubMed:15322419]
  5. Williard RL, Middaugh LD, Zhu HJ, Patrick KS: Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity. Behav Pharmacol. 2007 Feb;18(1):39-51. [PubMed:17218796]
  6. Chuhan YS, Taukulis HK: Impairment of single-trial memory formation by oral methylphenidate in the rat. Neurobiol Learn Mem. 2006 Mar;85(2):125-31. Epub 2005 Oct 24. [PubMed:16246598]
  7. Gray JD, Punsoni M, Tabori NE, Melton JT, Fanslow V, Ward MJ, Zupan B, Menzer D, Rice J, Drake CT, Romeo RD, Brake WG, Torres-Reveron A, Milner TA: Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress. J Neurosci. 2007 Jul 4;27(27):7196-207. [PubMed:17611273]
  8. Sandoval V, Riddle EL, Ugarte YV, Hanson GR, Fleckenstein AE: Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model. J Neurosci. 2001 Feb 15;21(4):1413-9. [PubMed:11160413]
  9. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  10. Tilley MR, Gu HH: The effects of methylphenidate on knockin mice with a methylphenidate-resistant dopamine transporter. J Pharmacol Exp Ther. 2008 Nov;327(2):554-60. doi: 10.1124/jpet.108.141713. Epub 2008 Aug 12. [PubMed:18698001]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Dresel SH, Kung MP, Huang X, Plossl K, Hou C, Shiue CY, Karp J, Kung HF: In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates. Eur J Nucl Med. 1999 Apr;26(4):342-7. [PubMed:10199939]
  2. Izenwasser S, Coy AE, Ladenheim B, Loeloff RJ, Cadet JL, French D: Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine. Eur J Pharmacol. 1999 Jun 4;373(2-3):187-93. [PubMed:10414438]
  3. Stehouwer JS, Jarkas N, Zeng F, Voll RJ, Williams L, Owens MJ, Votaw JR, Goodman MM: Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. J Med Chem. 2006 Nov 16;49(23):6760-7. [PubMed:17154506]

Drug created on May 06, 2010 10:32 / Updated on October 10, 2018 21:55