Identification

Name
Tolcapone
Accession Number
DB00323  (APRD00445)
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase (COMT). It is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication. It is a yellow, odorless, non-hygroscopic, crystalline compound. Tolcapone is associated with a risk of hepatotoxicity. [Wikipedia]

Structure
Thumb
Synonyms
  • (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
  • 3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone
  • 3,4-Dihydroxy-5-nitro-4'-methylbenzophenone
  • 4'-Methyl-3,4-dihydroxy-5-nitrobenzophenone
  • Tolcapon
  • Tolcapona
  • Tolcapone
  • Tolcaponum
External IDs
Ro 40-7592
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TasmarTablet, film coated100 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet100 mgOralHoffmann La Roche1997-10-201999-01-11Canada
TasmarTablet, film coated100 mg/1OralValeant Pharmaceuticals North America2004-07-27Not applicableUs
TasmarTablet, film coated100 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet, film coated200 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet, film coated100 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet, film coated100 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet, film coated200 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet, film coated100 mgOralMeda Ab1997-08-27Not applicableEu
TasmarTablet200 mgOralHoffmann La Roche1997-10-201999-01-11Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TolcaponeTablet, coated100 mg/1OralPar Pharmaceutical2015-01-06Not applicableUs
TolcaponeTablet100 mg/1OralIngenus Pharmaceuticals, LLC2018-08-21Not applicableUs
TolcaponeTablet, film coated100 mg/1OralOceanside Pharmaceuticals2004-07-27Not applicableUs
International/Other Brands
Sen De Ning (Dexin Runsheng Pharmaceutical)
Categories
UNII
CIF6334OLY
CAS number
134308-13-7
Weight
Average: 273.2408
Monoisotopic: 273.063722467
Chemical Formula
C14H11NO5
InChI Key
MIQPIUSUKVNLNT-UHFFFAOYSA-N
InChI
InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3
IUPAC Name
5-(4-methylbenzoyl)-3-nitrobenzene-1,2-diol
SMILES
CC1=CC=C(C=C1)C(=O)C1=CC(=C(O)C(O)=C1)[N+]([O-])=O

Pharmacology

Indication

Used as an adjunct to levodopa/carbidopa therapy for the symptomatic treatment of Parkinson's Disease. This drug is generally reserved for patients with parkinsonian syndrome receiving levodopa/carbidopa who are experiencing symptom fluctuations and are not responding adequately to or are not candidates for other adjunctive therapies.

Associated Conditions
Pharmacodynamics

Tolcapone is a potent, selective, and reversible inhibitor of catechol-O-methyltransferase (COMT). In humans, COMT is distributed throughout various organs. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa.

Mechanism of action

The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa, resulting in an increase in plasma levodopa concentrations. The inhibition of COMT also causes a reduction in circulating 3-OMD as a result of decreased peripheral metabolism of levodopa. This may lead to an increase distribution of levodopa into the CNS through the reduction of its competitive substrate, 3-OMD, for transport mechanisms. Sustained levodopa concentrations presumably result in more consistent dopaminergic stimulation, resulting in greater reduction in the manifestations of parkinsonian syndrome.

TargetActionsOrganism
ACatechol O-methyltransferase
inhibitor
Human
Absorption

Rapidly absorbed (absolute bioavailability is about 65%)

Volume of distribution
  • 9 L
Protein binding

> 99.9% (to serum albumin)

Metabolism

The main metabolic pathway of tolcapone is glucuronidation

Route of elimination

Tolcapone is almost completely metabolized prior to excretion, with only a very small amount (0.5% of dose) found unchanged in urine. The glucuronide conjugate of tolcapone is mainly excreted in the urine but is also excreted in the bile.

Half life

2-3.5 hours

Clearance
  • 7 L/h
Toxicity

LD50 = 1600 mg/kg (Orally in rats)

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

Interactions

Drug Interactions
DrugInteraction
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Tolcapone.
2-HydroxyestradiolThe metabolism of 2-Hydroxyestradiol can be decreased when combined with Tolcapone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Tolcapone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Tolcapone is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Tolcapone is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Tolcapone is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Tolcapone is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Tolcapone is combined with 7-Nitroindazole.
AbacavirTolcapone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Tolcapone which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. [PubMed:9917075]
  2. Keating GM, Lyseng-Williamson KA: Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005;19(2):165-84. [PubMed:15697329]
  3. Truong DD: Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease. Clin Interv Aging. 2009;4:109-13. Epub 2009 May 14. [PubMed:19503773]
  4. Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Jarvinen T, Mannisto PT: Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther. 2003 Feb;304(2):498-506. [PubMed:12538800]
  5. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [PubMed:10882160]
External Links
Human Metabolome Database
HMDB0014468
KEGG Drug
D00786
KEGG Compound
C07949
PubChem Compound
4659569
PubChem Substance
46504932
ChemSpider
3848682
BindingDB
50108877
ChEBI
63630
ChEMBL
CHEMBL1324
Therapeutic Targets Database
DAP000607
PharmGKB
PA451720
HET
TCW
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Tolcapone
ATC Codes
N04BX01 — Tolcapone
PDB Entries
3s68 / 4d7b / 4pyl / 5a6i
FDA label
Download (71.3 KB)
MSDS
Download (17.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0Enrolling by InvitationTreatmentAmyloidosis, Leptomeningeal, Transthyretin-Related / Transthyretin Amyloidosis1
1Active Not RecruitingOtherHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers1
1RecruitingTreatmentMedulloblastomas / Neuroblastomas1
1Unknown StatusTreatmentCocaine-Related Disorders1
2Active Not RecruitingTreatmentFrontotemporal Lobar Degeneration1
2CompletedTreatmentNicotine Dependence1
2CompletedTreatmentPathological Gambling1
2CompletedTreatmentTobacco Use Disorders1
2Enrolling by InvitationTreatmentBrain Injuries,Traumatic / Brain Injury / Mild Cognitive Impairment (MCI) / Neurocognitive Disorders1
2RecruitingBasic ScienceAlcohol Abuse / Impulsive Behaviors1
2RecruitingTreatmentAlcohol Use Disorder (AUD)1
2TerminatedOtherSchizophrenic Disorders1
2, 3RecruitingTreatmentObsessive Compulsive Disorder (OCD)1
4CompletedTreatmentParkinson's Disease (PD)1
Not AvailableActive Not RecruitingBasic ScienceAddictions1
Not AvailableActive Not RecruitingBasic ScienceImpulsive Behaviors1
Not AvailableCompletedBasic SciencePathological Gambling1
Not AvailableRecruitingNot AvailableAtypical Parkinson Disease / Corticobasal Degeneration / Gait, Frontal / Multiple System Atrophy (MSA) / Parkinson's Disease (PD) / Parkinsonian Disorders / Progressive Supranuclear Palsy (PSP)1
Not AvailableRecruitingBasic ScienceMild Traumatic Brain Injury (MTBI)1
Not AvailableRecruitingTreatmentNicotine Dependence1

Pharmacoeconomics

Manufacturers
  • Valeant pharmaceuticals international
Packagers
  • Legacy Pharmaceuticals Packaging LLC
  • Murfreesboro Pharmaceutical Nursing Supply
  • Valeant Ltd.
Dosage forms
FormRouteStrength
TabletOral100 mg
TabletOral200 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral100 mg
Tablet, film coatedOral200 mg/1
Tablet, film coatedOral200 mg
TabletOral100 mg/1
Tablet, coatedOral100 mg/1
Prices
Unit descriptionCostUnit
Tasmar 100 mg tablet8.13USD tablet
Tasmar 200 mg tablet7.44USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5476875No1995-12-192012-12-19Us
US5236952No1993-08-172012-01-29Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0569 mg/mLALOGPS
logP2.63ALOGPS
logP3.28ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)5.17ChemAxon
pKa (Strongest Basic)-6.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area103.35 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity72.96 m3·mol-1ChemAxon
Polarizability26.44 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9041
Blood Brain Barrier-0.9418
Caco-2 permeable-0.5422
P-glycoprotein substrateNon-substrate0.6612
P-glycoprotein inhibitor INon-inhibitor0.6371
P-glycoprotein inhibitor IINon-inhibitor0.9128
Renal organic cation transporterNon-inhibitor0.933
CYP450 2C9 substrateNon-substrate0.6554
CYP450 2D6 substrateNon-substrate0.894
CYP450 3A4 substrateSubstrate0.5245
CYP450 1A2 substrateNon-inhibitor0.9199
CYP450 2C9 inhibitorInhibitor0.8317
CYP450 2D6 inhibitorNon-inhibitor0.9135
CYP450 2C19 inhibitorNon-inhibitor0.8762
CYP450 3A4 inhibitorNon-inhibitor0.6585
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5984
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.6079
BiodegradationNot ready biodegradable0.9433
Rat acute toxicity2.2574 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8346
hERG inhibition (predictor II)Non-inhibitor0.8311
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00e9-0980000000-495401c19ad2c2091c1a

Taxonomy

Description
This compound belongs to the class of organic compounds known as benzophenones. These are organic compounds containing a ketone attached to two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzophenones
Direct Parent
Benzophenones
Alternative Parents
Aryl-phenylketones / Diphenylmethanes / Nitrophenols / Nitrobenzenes / Benzoyl derivatives / Catechols / Nitroaromatic compounds / Toluenes / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids
show 6 more
Substituents
Benzophenone / Diphenylmethane / Aryl-phenylketone / Nitrophenol / Nitrobenzene / Nitroaromatic compound / Benzoyl / Catechol / Aryl ketone / 1-hydroxy-4-unsubstituted benzenoid
show 18 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
benzophenones (CHEBI:63630) / a small molecule (CPD-7664)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
O-methyltransferase activity
Specific Function
Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOP...
Gene Name
COMT
Uniprot ID
P21964
Uniprot Name
Catechol O-methyltransferase
Molecular Weight
30036.77 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Ries V, Selzer R, Eichhorn T, Oertel WH, Eggert K: Replacing a dopamine agonist by the COMT-inhibitor tolcapone as an adjunct to L-dopa in the treatment of Parkinson's disease: a randomized, multicenter, open-label, parallel-group study. Clin Neuropharmacol. 2010 May;33(3):142-50. doi: 10.1097/WNF.0b013e3181d99d6f. [PubMed:20502133]
  3. Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. [PubMed:9917075]
  4. Keating GM, Lyseng-Williamson KA: Tolcapone: a review of its use in the management of Parkinson's disease. CNS Drugs. 2005;19(2):165-84. [PubMed:15697329]
  5. Truong DD: Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease. Clin Interv Aging. 2009;4:109-13. Epub 2009 May 14. [PubMed:19503773]
  6. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR: Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. Epub 2006 Oct 25. [PubMed:17063156]
  7. Stocchi F, De Pandis MF: Utility of tolcapone in fluctuating Parkinson's disease. Clin Interv Aging. 2006;1(4):317-25. [PubMed:18046910]
  8. Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Jarvinen T, Mannisto PT: Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther. 2003 Feb;304(2):498-506. [PubMed:12538800]
  9. Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson's disease. Acta Med Okayama. 2002 Feb;56(1):1-6. [PubMed:11873938]
  10. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [PubMed:10882160]
  11. Ruottinen HM, Rinne UK: COMT inhibition in the treatment of Parkinson's disease. J Neurol. 1998 Nov;245(11 Suppl 3):P25-34. [PubMed:9808337]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Jorga KM, Fotteler B, Gasser R, Banken L, Birnboeck H: Lack of interaction between tolcapone and tolbutamide in healthy volunteers. J Clin Pharmacol. 2000 May;40(5):544-51. [PubMed:10806608]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:41