TOLCAPONE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H11NO5
Molecular Weight	273.2408
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(C=C1)C(=O)C2=CC(=C(O)C(O)=C2)[N+]([O-])=O

InChI

InChIKey=MIQPIUSUKVNLNT-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00323
Curator's Comment: Description was created based on several sources, including

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. 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. Tolcapone is 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. Tolcapone is sold under the brand name Tasmar.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Catechol O-methyltransferase 21 Target ID: CHEMBL2023 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf	Inhibitor 8297		151.0 nM [IC50]
NCI-H1299 3 Target ID: CHEMBL612255 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24148818	Inhibitor 8297		29.3 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Idiopathic Parkinson's disease 19 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf	Secondary		Approved 8429	Tasmar Approved Use TASMAR is indicated as an adjunct to levodopa and carbidopa for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. Because of the risk of potentially fatal, acute fulminant liver failure, TASMAR (tolcapone) should ordinarily be used in patients with Parkinson’s disease on l-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. Because of the risk of liver injury and because TASMAR, when it is effective, provides an observable symptomatic benefit, the patient who fails to show substantial clinical benefit within 3 weeks of initiation of treatment, should be withdrawn from TASMAR. Launch Date 1998

C_max

Value	Dose	Analyte	Population
0.3 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
0.7 mg/L REVIEW https://pubmed.ncbi.nlm.nih.gov/7768073	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
4.6 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
6.3 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.3 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
13.4 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FASTED
2.4 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
20.3 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
0.5 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.1 mg × h/L REVIEW https://pubmed.ncbi.nlm.nih.gov/7768073	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
12.2 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
18.5 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2.8 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
43.8 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FASTED
5.7 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
67.7 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
1.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	5 mg single, oral dose: 5 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.7 h REVIEW https://pubmed.ncbi.nlm.nih.gov/7768073	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
1.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
2.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FASTED
1.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
3.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7768073	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered:	TOLCAPONE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf	unknown, unknown		TOLCAPONE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
800 mg 3 times / day multiple, oral Overdose Dose: 800 mg, 3 times / day Route: oral Route: multiple Dose: 800 mg, 3 times / day Co-administed with:: L-dopa, po(100 mg, tid) carbidopa, po(25 mg, tid) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106	healthy, 55 - 75 n = 6 Health Status: healthy Age Group: 55 - 75 Sex: M+F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (severe, 33%) Vomiting (severe, 33%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106
800 mg 3 times / day multiple, oral Overdose Dose: 800 mg, 3 times / day Route: oral Route: multiple Dose: 800 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.25	healthy Health Status: healthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.25	Disc. AE: Dizziness... AEs leading to discontinuation/dose reduction: Dizziness Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.25
200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21, p.12	unhealthy n = 592 Health Status: unhealthy Condition: Parkinson’s disease Population Size: 592 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21, p.12	Disc. AE: Diarrhea... AEs leading to discontinuation/dose reduction: Diarrhea (6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21, p.12
200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21	Disc. AE: Acute liver failure, Hepatocellular injury... AEs leading to discontinuation/dose reduction: Acute liver failure (grade 3-5) Hepatocellular injury (grade 3-5) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21
200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10	Disc. AE: ALT increased, Aspartate aminotransferase increased... AEs leading to discontinuation/dose reduction: ALT increased (1.7%) Aspartate aminotransferase increased (1.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10
200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.11	Disc. AE: Somnolence... AEs leading to discontinuation/dose reduction: Somnolence (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.11
200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21	Disc. AE: Hallucinations... AEs leading to discontinuation/dose reduction: Hallucinations (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21

AEs

AE	Significance	Dose	Population
Nausea	severe, 33% Disc. AE	800 mg 3 times / day multiple, oral Overdose Dose: 800 mg, 3 times / day Route: oral Route: multiple Dose: 800 mg, 3 times / day Co-administed with:: L-dopa, po(100 mg, tid) carbidopa, po(25 mg, tid) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106	healthy, 55 - 75 n = 6 Health Status: healthy Age Group: 55 - 75 Sex: M+F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106
Vomiting	severe, 33% Disc. AE	800 mg 3 times / day multiple, oral Overdose Dose: 800 mg, 3 times / day Route: oral Route: multiple Dose: 800 mg, 3 times / day Co-administed with:: L-dopa, po(100 mg, tid) carbidopa, po(25 mg, tid) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106	healthy, 55 - 75 n = 6 Health Status: healthy Age Group: 55 - 75 Sex: M+F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf https://pubmed.ncbi.nlm.nih.gov/9333106
Dizziness	Disc. AE	800 mg 3 times / day multiple, oral Overdose Dose: 800 mg, 3 times / day Route: oral Route: multiple Dose: 800 mg, 3 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.25	healthy Health Status: healthy Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.25
Diarrhea	6% Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21, p.12	unhealthy n = 592 Health Status: unhealthy Condition: Parkinson’s disease Population Size: 592 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21, p.12
Acute liver failure	grade 3-5 Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21
Hepatocellular injury	grade 3-5 Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.1, p.21
ALT increased	1.7% Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10
Aspartate aminotransferase increased	1.7% Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.10
Somnolence	1% Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.11
Hallucinations	1% Disc. AE	200 mg 3 times / day multiple, oral Recommended Dose: 200 mg, 3 times / day Route: oral Route: multiple Dose: 200 mg, 3 times / day Co-administed with:: L-dopa, po carbidopa, po Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21	unhealthy Health Status: unhealthy Condition: Parkinson’s disease Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020697s004lbl.pdf Page: p.21

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 214 CYP2A6 707 CYP1A2 1524 CYP2C19 1478	CYP2A6 543

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P4.pdf#page=27 Page: 27.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P4.pdf#page=27 Page: 27.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P4.pdf#page=27 Page: 27.0	yes [Ki 21 uM]
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P4.pdf#page=27 Page: 27.0	yes [Ki 30 uM]
CYP3A 298	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P4.pdf#page=27 Page: 27.0	yes [Ki 49 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P1.pdf#page=12 Page: 12.0	yes [Ki 7.4 uM]	yes (co-administration study) Comment: co-administration of tolcapone did not change the pharmakokinetics of tolcapone Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20697_Tasmar_pharmr_P1.pdf#page=12 Page: 12.0

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020697s013s015lbl.pdf#page=4 Page: 4.0	yes [Km 7 uM]
CYP2A6 543	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020697s013s015lbl.pdf#page=4 Page: 4.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63630	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63630
ChemicalBook	CB9302569	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB9302569
MolPort	MolPort-003-850-570	https://www.molport.com/shop/molecule-link/MolPort-003-850-570
Selleck Chemicals	tolcapone	http://www.selleckchem.com/products/tolcapone.html
ZINC	ZINC000035342789	http://zinc15.docking.org/substances/ZINC000035342789
eMolecules	2735694	https://www.emolecules.com/cgi-bin/more?vid=2735694

PubMed

Title	Date	PubMed
Inhibition of catechol-O-methyltransferase (COMT) in the brain does not affect the action of dopamine and levodopa: an in vitro electrophysiological evidence from rat mesencephalic dopamine neurons.	1999	10651109
Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.	1999 Jan-Feb	10047930
Neuroleptic malignant-like syndrome in an elderly patient caused by abrupt withdrawal of tolcapone, a-catechol-o-methyl transferase inhibitor.	2000 Apr 15	10866587
Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease.	2000 Jun	10882160
Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.	2000 Jun	10872643
[Akathisia secondary to tolcapone. Report of a case].	2000 Sep-Oct	11080934
COMT inhibition and safety.	2001	11996508
Neuroleptic malignant-like syndrome and acute hepatitis during tolcapone and clozapine medication.	2001	11598337
Switch-over from tolcapone to entacapone in severe Parkinson's disease patients.	2001	11455177
Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.	2001	11432539
The central catechol-O-methyltransferase inhibitor tolcapone increases striatal hydroxyl radical production in L-DOPA/carbidopa treated rats.	2001	11314772
Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.	2001	11261749
Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease.	2001 Apr	11248589
Possible applications for dopaminergic agents following traumatic brain injury: part 2.	2001 Feb	11277855
Gait analysis in advanced Parkinson's disease--effect of levodopa and tolcapone.	2001 Feb	11252300
Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase.	2001 Feb	11160877
Catechol-O-methyltransferase decreases levodopa toxicity in vitro.	2001 Jan-Feb	11290879
D1-like dopamine receptor activation and natriuresis by nitrocatechol COMT inhibitors.	2001 May	11318939
Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson's disease patients with motor fluctuations.	2001 Sep	11746615
Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease.	2001 Sep-Oct	11586115
Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.	2002	12439739
[The usefulness of dopaminergic drugs in traumatic brain injury].	2002 Aug 16-31	12235569
Entacapone in the management of Parkinson's disease.	2002 Jul	12083995
Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.	2002 May	12111468
Mechanisms of idiosyncratic drug reactions: the case of felbamate.	2002 Nov 10	12399158
Effects of entacapone and tolcapone on mitochondrial membrane potential.	2002 Oct 18	12393055
Tolcapone-related liver dysfunction: implications for use in Parkinson's disease therapy.	2003	12908845
Advances in the pharmacological management of Parkinson disease.	2003	12830929
Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice.	2003 Jul-Aug	12884403
Cerebrospinal fluid 3,4-dihydroxyphenylacetic acid level after tolcapone administration as an indicator of nigrostriatal degeneration.	2003 Sep	12957500
Safety and tolerability of COMT inhibitors.	2004 Jan 13	14718679
Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex.	2004 Jun 9	15190105
Clinical advantages of COMT inhibition with entacapone - a review.	2004 Oct	15340869
Catechol-O-methyltransferase inhibitors for levodopa-induced complications in Parkinson's disease.	2004 Oct 18	15495119
Catechol-O-methyltransferase inhibitors versus active comparators for levodopa-induced complications in Parkinson's disease.	2004 Oct 18	15495118
Role of COMT inhibitors and dopamine agonists in the treatment of motor fluctuations.	2005	15822107
Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy.	2005 Jan	15709899
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942
Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004.	2005 May	15818599
Pharmacokinetic optimisation in the treatment of Parkinson's disease : an update.	2006	16485914
Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson's disease patients.	2006 Jun	16758261
Tolcapone in the management of Parkinson's disease.	2006 Nov	17059382
Bioactivation and hepatotoxicity of nitroaromatic drugs.	2006 Oct	17073576
Entacapone to tolcapone switch: Multicenter double-blind, randomized, active-controlled trial in advanced Parkinson's disease.	2007 Jan	17089403
Tolcapone improves cognition and cortical information processing in normal human subjects.	2007 May	17063156
Safety and tolerability of adjunctive tolcapone treatment in patients with early Parkinson's disease.	2007 Sep	17098835

Patents

Sample Use Guides

In Vivo Use Guide

The initial dose of TASMAR is always 100 mg three times per day. The recommended daily dose of TASMAR is also 100 mg tid.

Route of Administration: Oral

In Vitro Use Guide

When using a fixed amount of total protein (2 ug/ml), but variable concentrations of COMT, the inhibitory potency of tolcapone upon S- and MB-COMT activity in the rat brain was in the low nM range (IC50's of 2 and 3 nM, respectively), whereas in rat liver the IC50 values for tolcapone against liver MB- and S-COMT (IC50's of 123 and 795 nM, respectively) were markedly higher than those observed in the brain. By contrast, when inhibition studies were performed with a fixed concentration of COMT (15 nM), tolcapone was found to be endowed with the same potency (in the low nM range) in inhibiting S- and MB-COMT from both brain and liver.

Name

Type

Language

TOLCAPONE

Official Name

English

Tolcapone [WHO-DD]

Common Name

English

RO-407592

Code

English

TOLCAPONE [USP MONOGRAPH]

Common Name

English

TOLCAPONE [MI]

Common Name

English

TOLCAPONE [MART.]

Common Name

English

TOLCAPONE [ORANGE BOOK]

Common Name

English

TOLCAPONE [USAN]

Common Name

English

RO-40-7592

Code

English

TOLCAPONE [JAN]

Common Name

English

TOLCAPONE [EMA EPAR]

Common Name

English

RO 40-7592

Code

English

3,4-DIHYDROXY-4'-METHYL-5-NITROBENZOPHENONE

Systematic Name

English

tolcapone [INN]

Common Name

English

TOLCAPONE [VANDF]

Common Name

English

TOLCAPONE [USP-RS]

Common Name

English

TASMAR

Brand Name

English

METHANONE, (3,4-DIHYDROXY-5-NITROPHENYL)(4-METHYLPHENYL)-

Systematic Name

English

Classification Tree Code System Code

EMA ASSESSMENT REPORTS

TASMAR (AUTHORIZED: PARKINSON DISEASE)