Identification
- Summary
Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used as adjunct therapy in the symptomatic management of idiopathic Parkinson's disease.
- Brand Names
- Tasmar
- Generic Name
- Tolcapone
- DrugBank Accession Number
- DB00323
- Background
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.
- Type
- Small Molecule
- Groups
- Approved, Withdrawn
- Structure
Structure for Tolcapone (DB00323)
- Weight
- Average: 273.2408
Monoisotopic: 273.063722467 - Chemical Formula
- C14H11NO5
- 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
- RO-40-7592
- RO-407592
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.
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in management of Idiopathic parkinson's disease •••••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism ACatechol O-methyltransferase inhibitorHumans - 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
- Adverse Effects
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LD50 = 1600 mg/kg (Orally in rats)
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of CNS depression can be increased when Tolcapone is combined with 1,2-Benzodiazepine. Abacavir Tolcapone may decrease the excretion rate of Abacavir which could result in a higher serum level. Abaloparatide The risk or severity of adverse effects can be increased when Tolcapone is combined with Abaloparatide. Acebutolol The risk or severity of adverse effects can be increased when Tolcapone is combined with Acebutolol. Aceclofenac Aceclofenac may decrease the excretion rate of Tolcapone which could result in a higher serum level. - Food Interactions
- Take with or without food. There is a 10-20% reduction in oral bioavailability when food is given 1 hour before and 2 hours after tolcapone.
Products
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- Sen De Ning (Dexin Runsheng Pharmaceutical)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tasmar Tablet, film coated 200 mg Oral Viatris Healthcare Limited 2016-09-08 Not applicable EU 
Tasmar Tablet, film coated 100 mg Oral Viatris Healthcare Limited 2016-09-08 Not applicable EU Tasmar Tablet 200 mg / tab Oral Hoffmann La Roche 1997-10-20 1999-01-11 Canada 
Tasmar Tablet, film coated 100 mg Oral Viatris Healthcare Limited 2016-09-08 Not applicable EU Tasmar Tablet, film coated 200 mg/1 Oral Valeant Pharmaceuticals International 2006-10-05 2006-10-05 US 
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Tolcapone Tablet, film coated 100 mg/1 Oral Oceanside Pharmaceuticals 2004-07-27 Not applicable US Tolcapone Tablet, coated 100 mg/1 Oral Par Pharmaceutical, Inc. 2015-01-06 Not applicable US Tolcapone Tablet 100 mg/1 Oral Ingenus Pharmaceuticals, LLC 2018-08-21 Not applicable US
Categories
- ATC Codes
- N04BX01 — Tolcapone
- Drug Categories
- Anti-Dyskinesia Agents
- Anti-Parkinson Drugs
- Benzene Derivatives
- Benzophenones
- Central Nervous System Agents
- Central Nervous System Depressants
- COMT Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inhibitors
- Dopamine Agents
- Drugs that are Mainly Renally Excreted
- Enzyme Inhibitors
- Hypotensive Agents
- Ketones
- Nervous System
- Nitro Compounds
- Nitrophenols
- Phenols
- Chemical TaxonomyProvided by Classyfire
- 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
- 1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / Allyl-type 1,3-dipolar organic compound / Aromatic homomonocyclic compound / Aryl ketone / Aryl-phenylketone / Benzophenone / Benzoyl / C-nitro compound / Catechol show 18 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- benzophenones (CHEBI:63630) / a small molecule (CPD-7664)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- CIF6334OLY
- CAS number
- 134308-13-7
- 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
References
- General References
- Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [Article]
- External Links
- Human Metabolome Database
- HMDB0014468
- KEGG Drug
- D00786
- KEGG Compound
- C07949
- PubChem Compound
- 4659569
- PubChem Substance
- 46504932
- ChemSpider
- 3848682
- BindingDB
- 50108877
- 72937
- ChEBI
- 63630
- ChEMBL
- CHEMBL1324
- ZINC
- ZINC000035342789
- Therapeutic Targets Database
- DAP000607
- PharmGKB
- PA451720
- PDBe Ligand
- TCW
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Tolcapone
- PDB Entries
- 3s68 / 4d7b / 4pyl / 5a6i / 6txv / 6txw / 6xtk / 7ybr / 8guv
- FDA label
- Download (71.3 KB)
- MSDS
- Download (17.3 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Parkinson's Disease (PD) 1 4 Withdrawn Basic Science Addiction 1 2 Completed Basic Science Alcohol Abuse / Impulsive Behaviors 1 2 Completed Treatment Alcohol Use Disorders (AUD) 1 2 Completed Treatment Frontotemporal Lobar Degeneration (FTLD) 1
Pharmacoeconomics
- Manufacturers
- Valeant pharmaceuticals international
- Packagers
- Legacy Pharmaceuticals Packaging LLC
- Murfreesboro Pharmaceutical Nursing Supply
- Valeant Ltd.
- Dosage Forms
Form Route Strength Tablet Oral 100 mg / tab Tablet Oral 200 mg / tab Tablet, film coated Oral 100 MG Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 200 mg/1 Tablet, film coated Oral 200 MG Tablet, coated Oral 100 mg Tablet Oral 100 mg/1 Tablet, coated Oral 100 mg/1 - Prices
Unit description Cost Unit Tasmar 100 mg tablet 8.13USD tablet Tasmar 200 mg tablet 7.44USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5476875 No 1995-12-19 2012-12-19 US US5236952 No 1993-08-17 2012-01-29 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 4 Not Available - Predicted Properties
Property Value Source Water Solubility 0.0569 mg/mL ALOGPS logP 2.63 ALOGPS logP 3.28 Chemaxon logS -3.7 ALOGPS pKa (Strongest Acidic) 5.59 Chemaxon pKa (Strongest Basic) -6.5 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 100.67 Å2 Chemaxon Rotatable Bond Count 3 Chemaxon Refractivity 71.96 m3·mol-1 Chemaxon Polarizability 26.89 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9041 Blood Brain Barrier - 0.9418 Caco-2 permeable - 0.5422 P-glycoprotein substrate Non-substrate 0.6612 P-glycoprotein inhibitor I Non-inhibitor 0.6371 P-glycoprotein inhibitor II Non-inhibitor 0.9128 Renal organic cation transporter Non-inhibitor 0.933 CYP450 2C9 substrate Non-substrate 0.6554 CYP450 2D6 substrate Non-substrate 0.894 CYP450 3A4 substrate Substrate 0.5245 CYP450 1A2 substrate Non-inhibitor 0.9199 CYP450 2C9 inhibitor Inhibitor 0.8317 CYP450 2D6 inhibitor Non-inhibitor 0.9135 CYP450 2C19 inhibitor Non-inhibitor 0.8762 CYP450 3A4 inhibitor Non-inhibitor 0.6585 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5984 Ames test Non AMES toxic 0.9132 Carcinogenicity Non-carcinogens 0.6079 Biodegradation Not ready biodegradable 0.9433 Rat acute toxicity 2.2574 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8346 hERG inhibition (predictor II) Non-inhibitor 0.8311
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0q29-3970000000-6534afd6ea55a8b8f923 LC-MS/MS Spectrum - LC-ESI-qTof , Positive LC-MS/MS splash10-00e9-0980000000-495401c19ad2c2091c1a MS/MS Spectrum - , positive LC-MS/MS splash10-00e9-0980000000-495401c19ad2c2091c1a Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 177.1653002 predictedDarkChem Lite v0.1.0 [M-H]- 162.848445 predictedDarkChem Lite v0.1.0 [M-H]- 176.8691002 predictedDarkChem Lite v0.1.0 [M-H]- 156.3532 predictedDeepCCS 1.0 (2019) [M+H]+ 176.6580002 predictedDarkChem Lite v0.1.0 [M+H]+ 172.8522737 predictedDarkChem Lite v0.1.0 [M+H]+ 176.9021002 predictedDarkChem Lite v0.1.0 [M+H]+ 158.74449 predictedDeepCCS 1.0 (2019) [M+Na]+ 176.8577002 predictedDarkChem Lite v0.1.0 [M+Na]+ 185.8954259 predictedDarkChem Lite v0.1.0 [M+Na]+ 176.7574002 predictedDarkChem Lite v0.1.0 [M+Na]+ 166.25374 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- 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
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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. [Article]
- Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson's disease. Pharmacotherapy. 1999 Jan;19(1):6-20. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Stocchi F, De Pandis MF: Utility of tolcapone in fluctuating Parkinson's disease. Clin Interv Aging. 2006;1(4):317-25. [Article]
- 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. [Article]
- Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson's disease. Acta Med Okayama. 2002 Feb;56(1):1-6. [Article]
- Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. [Article]
- Ruottinen HM, Rinne UK: COMT inhibition in the treatment of Parkinson's disease. J Neurol. 1998 Nov;245(11 Suppl 3):P25-34. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- Curator comments
- Inhibition observed in vitro - unlikely to be clinically relevant.
- 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
- 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. [Article]
Drug created at June 13, 2005 13:24 / Updated at November 03, 2023 23:40