DT-Web

DB00494 - Entacapone


Identification
Name Entacapone
Accession Number DB00494 (APRD00416)
Type small molecule
Description Entacapone is a selective, reversible catechol-O-methyl transferase (COMT) inhibitor for the treatment of Parkinson's disease. It is a member of the class of nitrocatechols. When administered concomittantly with levodopa and a decarboxylase inhibitor (e.g., carbidopa), increased and more sustained plasma levodopa concentrations are reached as compared to the administration of levodopa and a decarboxylase inhibitor.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 305.286
Groups approved
Monoisotopic Weight 305.101170605
Pharmacology
Indication Used as an adjunct to levodopa / carbidopa in the symptomatic treatment of patients with idiopathic Parkinson's Disease who experience the signs and symptoms of end-of-dose "wearing-off".
Mechanism of action The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.
Absorption Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.
Protein binding 98% (bind to serum albumin)
Biotransformation Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.
Route of elimination Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.
Toxicity Side effect include increase the occurrence of orthostatic hypotension, severe rhabdomyolysis, dyskinesia, hallucinations, hyperkinesia, hypokinesia, dizziness, fatigu,e gastrointestinal effects including abdominal pain constipation diarrhea nausea
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Apomorphine Entacapone increases the effect and toxicity of the sympathomimetic, apomorphine.
Bitolterol Entacapone may increase the effect and toxicity of bitolterol.
Dobutamine Entacapone increases the effect and toxicity of the sympathomimetic, dobutamine.
Dopamine Entacapone increases the effect and toxicity of the sympathomimetic, dopamine.
Epinephrine Entacapone may increase the effect and toxicity of the sympathomimetic, epinephrine.
Isocarboxazid Possible hypertensive crisis with this combination
Isoetharine Entacapone increases the effect and toxicity of the sympathomimetic, isoetharine.
Isoproterenol Entacapone increases the effect and toxicity of the sympathomimetic, isoproterenol.
Methyldopa Entacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.
Norepinephrine Entacapone increases the effect and toxicity of the sympathomimetic, norepinephrine.
Phenelzine Possible hypertensive crisis with this combination
Tranylcypromine Additive inhibition of endogenous catecholamine metabolism may increase the therapeutic/adverse effects of both agents. Concomitant therapy should be avoided.
Triprolidine The CNS depressants, Triprolidine and Entacapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Food Interactions
  • Take without regard to meals.

Targets


Catechol O-methyltransferase
Name Catechol O-methyltransferase
Gene Name COMT
Pharmacological action yes
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Najib J: Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clin Ther. 2001 Jun;23(6):802-32; discussion 771. - Pubmed
  • Chong BS, Mersfelder TL: Entacapone. Ann Pharmacother. 2000 Sep;34(9):1056-65. - Pubmed
  • Holm KJ, Spencer CM: Entacapone. A review of its use in Parkinson's disease. Drugs. 1999 Jul;58(1):159-77. - Pubmed
  • Poewe WH, Deuschl G, Gordin A, Kultalahti ER, Leinonen M: Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand. 2002 Apr;105(4):245-55. - Pubmed
  • Brooks DJ, Sagar H: Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry. 2003 Aug;74(8):1071-9. - Pubmed
  • 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
  • Tai CH, Wu RM: Catechol-O-methyltransferase and Parkinson's disease. Acta Med Okayama. 2002 Feb;56(1):1-6. - Pubmed
  • Kaakkola S: Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. Drugs. 2000 Jun;59(6):1233-50. - Pubmed
  • Ruottinen HM, Rinne UK: COMT inhibition in the treatment of Parkinson's disease. J Neurol. 1998 Nov;245(11 Suppl 3):P25-34. - Pubmed
DTHybrid score 0.796

Enzymes


Catechol O-methyltransferase
Name Catechol O-methyltransferase
Gene Name COMT
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
DTHybrid score 0.796
UDP-glucuronosyltransferase 1-9
Name UDP-glucuronosyltransferase 1-9
Gene Name UGT1A9
Actions substrate
References
  • -
  • Lautala P, Ethell BT, Taskinen J, Burchell B: The specificity of glucuronidation of entacapone and tolcapone by recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2000 Nov;28(11):1385-9. - Pubmed
  • Kurkela M, Garcia-Horsman JA, Luukkanen L, Morsky S, Taskinen J, Baumann M, Kostiainen R, Hirvonen J, Finel M: Expression and characterization of recombinant human UDP-glucuronosyltransferases (UGTs). UGT1A9 is more resistant to detergent inhibition than other UGTs and was purified as an active dimeric enzyme. J Biol Chem. 2003 Feb 7;278(6):3536-44. Epub 2002 Nov 14. - Pubmed
  • Luukkanen L, Taskinen J, Kurkela M, Kostiainen R, Hirvonen J, Finel M: Kinetic characterization of the 1A subfamily of recombinant human UDP-glucuronosyltransferases. Drug Metab Dispos. 2005 Jul;33(7):1017-26. Epub 2005 Mar 31. - Pubmed
DTHybrid score 0.2363

Predictions


Id Partner name Gene Name Score
4757 Cytochrome P450 2C9 CYP2C9 0.0665
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0542
5455 Arylsulfatase A ARSA 0.0518
20 Prostaglandin G/H synthase 1 PTGS1 0.0391
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0353
4512 Cytochrome P450 3A4 CYP3A4 0.032
290 Prostaglandin G/H synthase 2 PTGS2 0.0257
3939 Amine oxidase [flavin-containing] B MAOB 0.025
3941 Amine oxidase [flavin-containing] A MAOA 0.0243
6016 Cytochrome P450 2C19 CYP2C19 0.0236
1588 Multidrug resistance protein 1 ABCB1 0.023
587 Serum albumin ALB 0.0211
146 Androgen receptor AR 0.021
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0202
193 Beta-1 adrenergic receptor ADRB1 0.0201
4200 Cytochrome P450 1A2 CYP1A2 0.0199
766 Beta-2 adrenergic receptor ADRB2 0.0195
6176 UDP-glucuronosyltransferase 1-3 UGT1A3 0.0189
6177 UDP-glucuronosyltransferase 1-10 UGT1A10 0.0186
318 Alpha-2A adrenergic receptor ADRA2A 0.0184
4924 Cytochrome P450 2C8 CYP2C8 0.0171
3866 Serum amyloid A protein SAA1 0.0163
1200 AMBP protein AMBP 0.0163
1932 Apolipoprotein E APOE 0.0163
6180 UDP-glucuronosyltransferase 2B4 UGT2B4 0.0157
4119 Cytochrome P450 2D6 CYP2D6 0.015
330 Spermidine synthase SRM 0.0149
3038 Spermidine synthase speE 0.0149
1729 Solute carrier family 22 member 6 SLC22A6 0.014
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.014
796 Inosine-5'-monophosphate dehydrogenase 2 IMPDH2 0.0139
838 Inosine-5'-monophosphate dehydrogenase 1 IMPDH1 0.0139
5718 Cytochrome P450 2A6 CYP2A6 0.0136
6102 Arylamine N-acetyltransferase 2 NAT2 0.0136
4604 Liver carboxylesterase 1 CES1 0.0132
113 S-adenosylmethionine decarboxylase proenzyme AMD1 0.0128
453 S-adenosylmethionine synthetase isoform type-1 MAT1A 0.0126
334 S-adenosylmethionine synthetase isoform type-2 MAT2A 0.0126
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0125
4118 Cytochrome P450 3A5 CYP3A5 0.0124
6013 Cytochrome P450 2E1 CYP2E1 0.0123
411 Glycine N-methyltransferase GNMT 0.0122
6181 UDP-glucuronosyltransferase 1-8 UGT1A8 0.0121
2164 Multidrug resistance-associated protein 4 ABCC4 0.0118
358 Cystathionine beta-synthase CBS 0.0117
467 Delta-type opioid receptor OPRD1 0.0106
696 Kappa-type opioid receptor OPRK1 0.0106
4132 Chloride channel protein ClC-Ka CLCNKA 0.0104
6107 Cytochrome P450 3A7 CYP3A7 0.0104
847 Mu-type opioid receptor OPRM1 0.0101
6025 UDP-glucuronosyltransferase 1-4 UGT1A4 0.0096
3809 Estrogen-related receptor gamma ESRRG 0.0095
738 Monocarboxylate transporter 1 SLC16A1 0.0092
4164 Potassium voltage-gated channel subfamily KQT member 5 KCNQ5 0.0083
4163 Potassium voltage-gated channel subfamily KQT member 4 KCNQ4 0.0083
243 Ribosyldihydronicotinamide dehydrogenase [quinone] NQO2 0.008
6030 Cytochrome P450 2B6 CYP2B6 0.0077
275 Arachidonate 5-lipoxygenase ALOX5 0.0076
6103 Arylamine N-acetyltransferase 1 NAT1 0.0076
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0075
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0074
238 Peroxisome proliferator-activated receptor gamma PPARG 0.0069
1757 Myeloperoxidase MPO 0.0069
136 Estrogen receptor ESR1 0.0069
862 Multidrug resistance-associated protein 1 ABCC1 0.0067
137 FolC bifunctional protein [Includes: Folylpolyglutamate synthase folC 0.0066
6500 Phospholipase A2 PLA2G1B 0.0063
4162 Potassium voltage-gated channel subfamily KQT member 3 KCNQ3 0.0063
6024 Cytochrome P450 1A1 CYP1A1 0.0062
489 Monocarboxylate transporter 2 SLC16A7 0.0062
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0061
723 Cytosolic phospholipase A2 PLA2G4A 0.0061
3811 Cytochrome P450 19A1 CYP19A1 0.006
1086 Potassium voltage-gated channel subfamily KQT member 2 KCNQ2 0.0059
638 D(3) dopamine receptor DRD3 0.0058
6106 Cytochrome P450 2C18 CYP2C18 0.0057
6142 Solute carrier family 22 member 8 SLC22A8 0.0057
54 Prothrombin F2 0.0056
6147 Solute carrier family 22 member 3 SLC22A3 0.0055
869 Estrogen receptor beta ESR2 0.0054
6155 ATP-binding cassette transporter sub-family C member 11 ABCC11 0.0053
40 RAF proto-oncogene serine/threonine-protein kinase RAF1 0.0052
1024 Solute carrier family 22 member 11 SLC22A11 0.0051
23 D(1A) dopamine receptor DRD1 0.0051
373 Transthyretin TTR 0.0051
26 Vascular endothelial growth factor receptor 3 FLT4 0.0049
891 Dihydropteroate synthase folP 0.0049
5359 Dihydropteroate synthase folP 0.0049
7175 Dihydropteroate synthase sulI 0.0049
4177 Proto-oncogene tyrosine-protein kinase receptor ret RET 0.0048
459 Retinoic acid receptor RXR-alpha RXRA 0.0048
831 D(2) dopamine receptor DRD2 0.0048
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0048
32 Vascular endothelial growth factor receptor 1 FLT1 0.0047
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0047
153 Dopamine beta-hydroxylase DBH 0.0047
3854 Basic fibroblast growth factor receptor 1 FGFR1 0.0045
6141 Sodium/bile acid cotransporter SLC10A1 0.0045
228 Beta platelet-derived growth factor receptor PDGFRB 0.0044
698 B-Raf proto-oncogene serine/threonine-protein kinase BRAF 0.0044
118 Organic cation/carnitine transporter 2 SLC22A5 0.0042
504 Mast/stem cell growth factor receptor KIT 0.0041
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.004
6149 Solute carrier family 22 member 10 SLC22A10 0.004
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0039
407 Vascular endothelial growth factor receptor 2 KDR 0.0038
102 DNA topoisomerase I, mitochondrial TOP1MT 0.0038
341 5-hydroxytryptamine 3 receptor HTR3A 0.0038
6167 Organic solute transporter subunit beta OSTB 0.0037
6166 Organic solute transporter subunit alpha OSTA 0.0037
163 D(1B) dopamine receptor DRD5 0.0036
4100 Gamma-aminobutyric-acid receptor subunit beta-2 GABRB2 0.0035
432 D(4) dopamine receptor DRD4 0.0034
4099 Gamma-aminobutyric-acid receptor subunit beta-3 GABRB3 0.0034
5798 Mitogen-activated protein kinase 11 MAPK11 0.0033
2021 Thrombomodulin THBD 0.0033
713 Sodium-dependent dopamine transporter SLC6A3 0.0033
824 Sodium-dependent serotonin transporter SLC6A4 0.0033
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0033
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0032
464 Glutamate [NMDA] receptor subunit epsilon-2 GRIN2B 0.0032
1353 DNA topoisomerase 1 TOP1 0.0032
3552 DNA topoisomerase 1 topA 0.0032
1192 Sulfotransferase 1A1 SULT1A1 0.0032
6160 Solute carrier organic anion transporter family member 3A1 SLCO3A1 0.0031
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0031
1275 Estrogen sulfotransferase SULT1E1 0.003
267 Plasminogen activator inhibitor 1 SERPINE1 0.003
1050 Bile salt sulfotransferase SULT2A1 0.0029
3802 Sodium channel protein type 2 subunit alpha SCN2A 0.0029
6221 Steroid hormone receptor ERR1 ESRRA 0.0029
6144 Solute carrier family 22 member 2 SLC22A2 0.0028
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0028
230 ATP-binding cassette transporter sub-family C member 8 ABCC8 0.0028
1039 Histone deacetylase 9 HDAC9 0.0027
3804 Sodium channel protein type 4 subunit alpha SCN4A 0.0027
6145 Solute carrier family 22 member 1 SLC22A1 0.0027
6143 Solute carrier family 22 member 7 SLC22A7 0.0027
3937 Fatty-acid amide hydrolase FAAH 0.0026
936 Ephrin type-A receptor 2 EPHA2 0.0025
6042 Prostaglandin reductase 2 PTGR2 0.0025
5787 Angiopoietin-1 receptor TEK 0.0025
165 FL cytokine receptor FLT3 0.0025
1618 High affinity nerve growth factor receptor NTRK1 0.0025
1457 Long-chain-fatty-acid--CoA ligase 4 ACSL4 0.0024
823 Fibroblast growth factor receptor 2 FGFR2 0.0024
630 Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial ACADSB 0.0024
950 Alpha platelet-derived growth factor receptor PDGFRA 0.0024
182 2-oxoglutarate dehydrogenase E1 component, mitochondrial OGDH 0.0024
1792 Tissue-type plasminogen activator PLAT 0.0023
6043 Putative G-protein coupled receptor 44 GPR44 0.0023
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0023
273 Apoptosis regulator Bcl-2 BCL2 0.0022
6085 Fatty acid-binding protein, intestinal FABP2 0.0022
1974 Oligopeptide transporter, kidney isoform SLC15A2 0.0022
170 Succinate semialdehyde dehydrogenase, mitochondrial ALDH5A1 0.002
502 5-hydroxytryptamine 2A receptor HTR2A 0.002
1313 Lactoylglutathione lyase GLO1 0.0019
3923 Cholinesterase BCHE 0.0019
17 Proto-oncogene tyrosine-protein kinase ABL1 ABL1 0.0019
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0019
280 4-aminobutyrate aminotransferase, mitochondrial ABAT 0.0018
2981 Phospholipase A2, membrane associated PLA2G2A 0.0018
6031 Cytochrome P450 3A43 CYP3A43 0.0018
6091 Gamma-aminobutyric acid receptor subunit theta GABRQ 0.0018
1898 Cytochrome P450 1B1 CYP1B1 0.0018
6137 Multidrug resistance-associated protein 6 ABCC6 0.0017
6086 Gamma-aminobutyric acid receptor subunit gamma-2 GABRG2 0.0016
6088 Gamma-aminobutyric acid receptor subunit gamma-3 GABRG3 0.0016
6115 Gamma-aminobutyric acid receptor subunit rho-3 GABRR3 0.0016
6092 Gamma-aminobutyric acid receptor subunit rho-2 GABRR2 0.0016
6090 Gamma-aminobutyric acid receptor subunit pi GABRP 0.0016
6093 Gamma-aminobutyric acid receptor subunit delta GABRD 0.0016
6087 Gamma-aminobutyric acid receptor subunit gamma-1 GABRG1 0.0016
6089 Gamma-aminobutyric acid receptor subunit epsilon GABRE 0.0016
142 Gamma-aminobutyric-acid receptor subunit rho-1 GABRR1 0.0016
4098 Gamma-aminobutyric-acid receptor subunit beta-1 GABRB1 0.0015
776 Bile salt export pump ABCB11 0.0015
841 Gamma-aminobutyric-acid receptor subunit alpha-6 GABRA6 0.0014
530 Gamma-aminobutyric-acid receptor subunit alpha-4 GABRA4 0.0014
580 Gamma-aminobutyric-acid receptor subunit alpha-3 GABRA3 0.0014
523 Gamma-aminobutyric-acid receptor subunit alpha-5 GABRA5 0.0014
423 Gamma-aminobutyric-acid receptor subunit alpha-2 GABRA2 0.0014
872 Gamma-aminobutyric-acid receptor subunit alpha-1 GABRA1 0.0013
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