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Identification
NameTolcapone
Accession NumberDB00323  (APRD00445)
Typesmall molecule
Groupsapproved, withdrawn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
SynonymLanguageCode
(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanoneNot AvailableIUPAC
TolcaponGermanINN
TolcaponaSpanishINN
TolcaponeNot AvailableUSAN, BAN, USP 34
TolcaponumLatinINN
SaltsNot Available
Brand names
NameCompany
Sen De NingDexin Runsheng Pharmaceutical
TasmarValeant
Brand mixturesNot Available
Categories
CAS number134308-13-7
WeightAverage: 273.2408
Monoisotopic: 273.063722467
Chemical FormulaC14H11NO5
InChI KeyMIQPIUSUKVNLNT-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-methylphenyl)carbonyl]-3-nitrobenzene-1,2-diol
SMILES
CC1=CC=C(C=C1)C(=O)C1=CC(=C(O)C(O)=C1)[N+]([O-])=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzophenones
Direct parentBenzophenones
Alternative parentsDiphenylmethanes; Nitrophenols and Derivatives; Acetophenones; Nitrobenzenes; Benzoyl Derivatives; Aminophenols; Catechols; Toluenes; Ketones; Polyols; Nitro Compounds; Nitronic Acids; Organic Oxoazanium Compounds; Enolates; Enols; Polyamines
Substituentsnitrophenol derivative; acetophenone; nitrobenzene; 1,2-diphenol; benzoyl; aminophenol; toluene; phenol derivative; nitronic acid; nitro compound; polyol; ketone; organic oxoazanium; enolate; polyamine; enol; carbonyl group; amine; organonitrogen compound
Classification descriptionThis compound belongs to the benzophenones. These are organic compounds containing a ketone attached to two phenyl groups.
Pharmacology
IndicationUsed 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.
PharmacodynamicsTolcapone 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 actionThe 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.
AbsorptionRapidly 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 eliminationTolcapone 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 life2-3.5 hours
Clearance
  • 7 L/h
ToxicityLD50 = 1600 mg/kg (Orally in rats)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 substrate Inhibitor 0.8317
CYP450 2D6 substrate Non-inhibitor 0.9135
CYP450 2C19 substrate Non-inhibitor 0.8762
CYP450 3A4 substrate 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
Pharmacoeconomics
Manufacturers
  • Valeant pharmaceuticals international
Packagers
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Prices
Unit descriptionCostUnit
Tasmar 100 mg tablet8.13USDtablet
Tasmar 200 mg tablet7.44USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States54768751992-12-192012-12-19
United States52369521995-01-292012-01-29
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP4Not Available
Predicted Properties
PropertyValueSource
water solubility5.69e-02 g/lALOGPS
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 area103.35ChemAxon
rotatable bond count3ChemAxon
refractivity72.96ChemAxon
polarizability26.44ChemAxon
number of rings2ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson’s disease. Pharmacotherapy. 1999 Jan;19(1):6-20. Pubmed
  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
  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
  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
  5. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs. 2000 Jun;59(6):1233-50. Pubmed
External Links
ResourceLink
KEGG DrugD00786
KEGG CompoundC07949
PubChem Compound4659569
PubChem Substance46504932
ChemSpider3848682
BindingDB50108877
Therapeutic Targets DatabaseDAP000607
PharmGKBPA451720
Drug Product Database2235914
RxListhttp://www.rxlist.com/cgi/generic3/tolcapone.htm
Drugs.comhttp://www.drugs.com/cdi/tolcapone.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/tas1426.shtml
WikipediaTolcapone
ATC CodesN04BX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(71.3 KB)
MSDSshow(17.3 KB)
Interactions
Drug Interactions
Drug
FurazolidoneTolcapone and Furazolidone decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
IsocarboxazidTolcapone and Isocarboxazid decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
LinezolidTolcapone and Linezolid decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
MoclobemideTolcapone and Moclobemide decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
PhenelzineTolcapone and Phenelzine decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
ProcarbazineTolcapone and Procarbazine decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
RasagilineTolcapone and Rasagiline decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
SelegilineTolcapone and Selegiline decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
TranylcypromineTolcapone and Tranylcypromine decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.
TriprolidineThe CNS depressants, Triprolidine and Tolcapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food InteractionsNot Available

Targets

1. Catechol O-methyltransferase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Catechol O-methyltransferase P21964 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Pubmed
  3. Guay DR: Tolcapone, a selective catechol-O-methyltransferase inhibitor for treatment of Parkinson’s disease. Pharmacotherapy. 1999 Jan;19(1):6-20. Pubmed
  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
  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
  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
  7. Stocchi F, De Pandis MF: Utility of tolcapone in fluctuating Parkinson’s disease. Clin Interv Aging. 2006;1(4):317-25. Pubmed
  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
  9. Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson’s disease. Acta Med Okayama. 2002 Feb;56(1):1-6. Pubmed
  10. Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease. Drugs. 2000 Jun;59(6):1233-50. Pubmed
  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

Enzymes

1. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on March 20, 2014 19:52