tolcapone 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | PK/Tox | Related Drugs | BioActivity |

Stem definitionDrug idCAS RN
catechol-O-methyltransferase (COMT) inhibitors 2697 134308-13-7

Description:

MoleculeDescription

Molfile Inchi Smiles

Synonyms:

  • RO 40-7592
  • tolcapone
  • tasmar
Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). 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. 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 patients.
  • Molecular weight: 273.24
  • Formula: C14H11NO5
  • CLOGP: 3.25
  • LIPINSKI: 0
  • HAC: 6
  • HDO: 2
  • TPSA: 103.35
  • ALOGS: -3.68
  • ROTB: 3
  • Status: OFP
    • Legend:
    OFP - off patent
    OFM - off market
    ONP - on patent

Drug dosage:

DoseUnitRoute
0.45 g O

ADMET properties:

PropertyValueReference
BDDCS (Biopharmaceutical Drug Disposition Classification System) 2 Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine) 0.50 % Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose) 12.20 µM/kg/day Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability) 62 % Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
Vd (Volume of distribution) 0.12 L/kg Lombardo F, Berellini G, Obach RS
CL (Clearance) 1.90 mL/min/kg Lombardo F, Berellini G, Obach RS
fu (Fraction unbound in plasma) 0.00 % Lombardo F, Berellini G, Obach RS
t_half (Half-life) 1.10 hours Lombardo F, Berellini G, Obach RS
S (Water solubility) 0.12 mg/mL Bocci G, Oprea TI, Benet LZ

Predicted pharmacokinetic/toxicological properties (PK-AZ):

PropertyDescriptionValueUnitConfidenceSimilarity
azlogd74 LogD at pH 7.4 0.505 High 1
caco2-efflux Caco-2 efflux ratio (BA/AB) 7.430 High 1
caco2-intrinsic-papp Caco-2 intrinsic apparent permeability 22.387 10^-6 cm/s High 1
dh-clint Dog hepatocyte intrinsic clearance 11.803 uL/min/10^6 cells High 1
dppb Dog plasma protein binding (% unbound) 1.020 % High 1
fcs-ppb Fetal calf serum protein binding (% unbound) 0.550 % High 1
herg hERG pIC50 4.734 pIC50 High 1
hh-clint Human hepatocyte intrinsic clearance 40.926 uL/min/10^6 cells High 1
hlm-clint Human liver microsomal intrinsic clearance 24.434 uL/min/mg protein High 1
hppb Human plasma protein binding (% unbound) 1.200 % High 1
kinase-safety-class ACVR2A,ACVR2B,ACVRL1,AKT2,AKT3,ALK,AURKA,AURKB,AXL,BRAF,BTK,CAMK2B,CAMK2D,CDK1,CDK4,CDK5,CDK9,CSF1R,DDR1,DYRK1B,EGFR,EIF2AK3,EPHB4,ERBB2,FGFR1,FLT3,GRK2,GRK3,GSK3B,IKBKB,ITK,JAK1,JAK2,JAK3,KIT,MAP2K6,MAP3K1,MAP3K14,MAP3K21,MAP3K7,MAP4K1,MAP4K3,MAPK1,MAPK10,MAPK12,MAPK14,MAPK7,MAPK8,MAPK9,MAPKAPK2,MAPKAPK5,MARK4,MELK,MET,MTOR,NTRK2,PDK1,PDK2,PDK4,PDPK1,PIK3CA,PIK3CB,PIK3CD,PIM2,PRKCD,PRKDC,SGK1,SIK2,SIK3,STK33,SYK,TEK,TGFBR1,TTK,ULK1,ZAP70 76
kinase-selectivity-class ACVR2A,ACVR2B,AXL,BRAF,CDK4,CDK9,DDR1,DYRK1B,EIF2AK3,EPHB4,ERBB2,GRK2,MAP2K6,MAPK1,MAPK12,MAPK7,MARK4,PDK4,PRKDC,SIK2,STK33,SYK,TEK,TTK 24
mdck-mdr1-efflux MDCK-MDR1 efflux ratio 9.750 High 1
mh-clint Mouse hepatocyte intrinsic clearance 30.620 High 1
mppb Mouse plasma protein binding (% unbound) 1.460 High 1
nih-mdck-mdr1-efflux NIH MDCK-MDR1 efflux ratio 1.040 High 1
pfas-class PFAS structural alert (1 = True, 0 = False) 0
pppb Pig plasma protein binding (% unbound) 0.570 % High 1
rh-clint Rat hepatocyte intrinsic clearance 63.680 uL/min/10^6 cells High 1
rh-fuinc Rat hepatocyte fraction unbound in incubation 54.990 % High 1
rppb Rat plasma protein binding (% unbound) 0.940 % High 1
solubility-dd Solubility at pH 7.4 in DMSO 872.971 uM High 1

Approvals:

DateAgencyCompanyOrphan
Jan. 29, 1998 FDA VALEANT PHARMS LLC

FDA Adverse Event Reporting System (Female)

None

FDA Adverse Event Reporting System (Male)

None

FDA Adverse Event Reporting System (Geriatric)

MedDRA adverse event termLikelihood ratioLikelihood ratio thresholdPatients taking drug having adverse eventPatients taking drug not having adverse eventPatients not taking drug having adverse eventPatients not taking drug not having adverse event
Hyperkinesia 65.79 50.29 11 350 3173 110585765
Gambling disorder 55.36 50.29 9 352 2182 110586756

FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

SourceCodeDescription
ATC N04BX01 NERVOUS SYSTEM
ANTI-PARKINSON DRUGS
DOPAMINERGIC AGENTS
Other dopaminergic agents
MeSH PA D000978 Antiparkinson Agents
MeSH PA D004791 Enzyme Inhibitors
MeSH PA D018726 Anti-Dyskinesia Agents
MeSH PA D065098 Catechol O-Methyltransferase Inhibitors
FDA MoA N0000175756 Catechol O-Methyltransferase Inhibitors
FDA EPC N0000175757 Catechol-O-Methyltransferase Inhibitor
CHEBI has role CHEBI:35476 antipsychotic agent
CHEBI has role CHEBI:35610 antineoplastic agent
CHEBI has role CHEBI:48406 EC 2.1.1.6 (catechol <em>O</em>-methyltransferase) inhibitor
CHEBI has role CHEBI:48407 antiparkinson drug
CHEBI has role CHEBI:63726 neuroprotective agent

Related Drugs by ATC class:

N04BX Other dopaminergic agents 3 drugs
budipineentacaponeopicapone

Drug Use | Suggest Off label Use Form| |View source of the data|

DiseaseRelationSNOMED_IDDOID
Parkinson's disease indication 49049000 DOID:14330
Hallucinations contraindication 7011001
Low blood pressure contraindication 45007003
Tardive dyskinesia contraindication 102449007
Liver function tests abnormal contraindication 166603001
Disease of liver contraindication 235856003 DOID:409
Rhabdomyolysis contraindication 240131006
Malignant melanoma contraindication 372244006
Severe diarrhea contraindication 409587002
Breastfeeding (mother) contraindication 413712001




🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation levelDissociation constantType (acidic/basic)
pKa1 4.84 acidic
pKa2 9.54 acidic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

TargetClassPharosUniProtActionTypeActivity value
(-log[M])		Mechanism
action		Bioact sourceMoA source
Catechol O-methyltransferase Enzyme INHIBITOR Ki 9.57 SCIENTIFIC LITERATURE CHEMBL
G-protein coupled receptor 35 GPCR EC50 5.13 CHEMBL
Transthyretin Secreted Kd 7.69 CHEMBL
Krueppel-like factor 10 Nuclear other IC50 4.30 CHEMBL
Catechol O-methyltransferase Enzyme IC50 8.66 CHEMBL
Bile salt export pump Transporter IC50 4.33 CHEMBL
Genome polyprotein [Cleaved into: Capsid protein C Enzyme IC50 6.19 CHEMBL

External reference:

IDSource
4021095 VUID
N0000148551 NUI
D00786 KEGG_DRUG
4021095 VANDF
C0246330 UMLSCUI
CHEBI:63630 CHEBI
TCW PDB_CHEM_ID
CHEMBL1324 ChEMBL_ID
DB00323 DRUGBANK_ID
D000077867 MESH_DESCRIPTOR_UI
4659569 PUBCHEM_CID
6646 IUPHAR_LIGAND_ID
6873 INN_ID
CIF6334OLY UNII
153657 RXNORM
11535 MMSL
234124 MMSL
5597 MMSL
d04282 MMSL
007040 NDDF
108464002 SNOMEDCT_US
386851002 SNOMEDCT_US
CIF6334OLY INXIGHT DRUGS

Pharmaceutical products:

ProductCategoryIngredientsNDCFormQuantityRouteMarketingLabel
Tasmar HUMAN PRESCRIPTION DRUG LABEL 1 0187-0938 TABLET, FILM COATED 100 mg ORAL NDA 27 sections
TOLCAPONE HUMAN PRESCRIPTION DRUG LABEL 1 50742-193 TABLET 100 mg ORAL ANDA 14 sections
Tolcapone HUMAN PRESCRIPTION DRUG LABEL 1 68682-938 TABLET, FILM COATED 100 mg ORAL NDA authorized generic 26 sections