Drug/Small Molecule:
tolcapone

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB has no annotated drug labels with pharmacogenomic information for this drug/small molecule. If you know of a drug label with PGx, send us a message.

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs3832043 -127delT, 10, 234580454delT, 526713delT, 855+34431delT, 855+53246delT, 87065delT, 9/, T, UGT1A9*22, UGT1A9:
T > -
5' Flanking
No VIP available No Clinical Annotations available VA
rs4680 1-5G>A, 19951271G>A, 27009G>A, 3103421G>A, 322G>A, 472G>A, COMP: Val158Met, COMT:Val108Met, Val108Met, Val158Met
G > A
5' Flanking
Val158Met
No VIP available No Clinical Annotations available VA
rs72551330 234580678T>C, 526937T>C, 855+34655T>C, 855+53470T>C, 87289T>C, 98T>C, Met33Thr
T > C
Missense
Met33Thr
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
Trade Names
  • Tasmar
Brand Mixture Names

PharmGKB Accession Id:
PA451720

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

Source: Drug Bank

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.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

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.

Source: Drug Bank

Pharmacology

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.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

The main metabolic pathway of tolcapone is glucuronidation

Source: Drug Bank

Protein Binding

> 99.9% (to serum albumin)

Source: Drug Bank

Absorption

Rapidly absorbed (absolute bioavailability is about 65%)

Source: Drug Bank

Half-Life

2-3.5 hours

Source: Drug Bank

Toxicity

LD 50 = 1600 mg/kg (Orally in rats)

Source: Drug Bank

Clearance

  • 7 L/h

Source: Drug Bank

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.

Source: Drug Bank

Volume of Distribution

  • 9 L

Source: Drug Bank

Chemical Properties

Chemical Formula

C14H11NO5

Source: Drug Bank

Isomeric SMILES

Cc1ccc(cc1)C(=O)c2cc(c(c(c2)O)O)N(=O)=O

Source: OpenEye

Canonical SMILES

CC1=CC=C(C=C1)C(=O)C1=CC(=C(O)C(O)=C1)[N+]([O-]

Source: Drug Bank

Average Molecular Weight

273.2408

Source: Drug Bank

Monoisotopic Molecular Weight

273.063722467

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
COMT
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
UGT1A9

Drug Targets

Gene Description
COMT (source: Drug Bank)

Drug Interactions

Drug Description
tolcapone Possible hypertensive crisis with this combination (source: Drug Bank)
tolcapone Possible hypertensive crisis with this combination (source: Drug Bank)
tolcapone Possible hypertensive crisis with this combination (source: Drug Bank)
tolcapone Possible hypertensive crisis with this combination (source: Drug Bank)
furazolidone Tolcapone 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. (source: Drug Bank)
isocarboxazid Tolcapone 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. (source: Drug Bank)
linezolid Tolcapone 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. (source: Drug Bank)
moclobemide Tolcapone 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. (source: Drug Bank)
phenelzine Tolcapone 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. (source: Drug Bank)
procarbazine Tolcapone 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. (source: Drug Bank)
rasagiline Tolcapone 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. (source: Drug Bank)
selegiline Tolcapone 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. (source: Drug Bank)
tranylcypromine Tolcapone 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. (source: Drug Bank)
tolcapone Additive inhibition of endogenous catecholamine metabolism may increase the therapeutic/adverse effects of both agents. Concomitant therapy should be avoided. (source: Drug Bank)
tolcapone The CNS depressants, Triprolidine and Tolcapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy. (source: Drug Bank)
tolcapone The CNS depressants, Triprolidine and Tolcapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy. (source: Drug Bank)

Curated Information ?

EvidenceDisease
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Parkinson Disease

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to tolcapone: 8

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Parkinson's disease pharmacogenomics: new findings and perspectives. Pharmacogenomics. 2014. Schumacher-Schuh Artur F, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effects of tolcapone on working memory and brain activity in abstinent smokers: A proof-of-concept study. Drug and alcohol dependence. 2013. Ashare Rebecca L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Anti-Parkinson's disease drugs and pharmacogenetic considerations. Expert opinion on drug metabolism & toxicology. 2013. AgĂșndez JosĂ© A G, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson's disease patients. European journal of clinical pharmacology. 2012. Ferrari Marco, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2011. Bitsios Panos, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2008. Giakoumaki Stella G, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Idiosyncratic drug hepatotoxicity. Nature reviews. Drug discovery. 2005. Kaplowitz Neil. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Med-psych drug-drug interactions update. Psychosomatics. 2002. Armstrong Scott C, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0187-0938-01
DrugBank:
DB00323
KEGG Compound:
C07949
KEGG Drug:
D00786
PubChem Compound:
4659569
PubChem Substance:
10150
46504932
Drugs Product Database (DPD):
2235914
BindingDB:
50108877
ChemSpider:
3848682
Therapeutic Targets Database:
DAP000607
FDA Drug Label at DailyMed:
a0e47a9d-78e7-4523-983a-aa259f221736

Clinical Trials

These are trials that mention tolcapone and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

Search PubMed
Search Medline Plus
Search PubChem
Search CTD

Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.