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药品详细

Tolcapone(托卡朋)

化学结构式图
中文名
托卡朋
英文名
Tolcapone
分子式
C14H11NO5
化学名
5-[(4-methylphenyl)carbonyl]-3-nitrobenzene-1,2-diol
分子量
Average: 273.2408
Monoisotopic: 273.063722467
CAS号
134308-13-7
ATC分类
N04B 未知
药物类型
small molecule
阶段
approved, withdrawn
商品名
Tasmar;
同义名
基本介绍

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]

生产厂家
  • Valeant pharmaceuticals international
封装厂家
参考
Synthesis Reference Not 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
剂型
规格
化合物类型
Type small molecule
Classes
  • Benzophenones
Substructures
  • Hydroxy Compounds
  • Phenols and Derivatives
  • Nitrobenzenes
  • Oxoazaniums
  • Nitrophenols and Derivatives
  • Benzene and Derivatives
  • Aminophenols and Derivatives
  • Nitro compounds
  • Catechols
  • Aromatic compounds
  • Benzophenones
  • Benzoyl Derivatives
  • Phenyl Esters
  • Anilines
  • Ketones
适应症
PARKINSON 帕金森氏症;
药理
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.
Pharmacodynamics 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.
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.
Absorption Rapidly 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 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.
Half life 2-3.5 hours
Clearance
  • 7 L/h
Toxicity LD50 = 1600 mg/kg (Orally in rats)
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
logP 4 Not Available
Predicted Properties
Property Value Source
water solubility 5.69e-02 g/l ALOGPS
logP 2.63 ALOGPS
logP 3.28 ChemAxon
logS -3.7 ALOGPS
pKa (strongest acidic) 5.17 ChemAxon
pKa (strongest basic) -6.4 ChemAxon
physiological charge -1 ChemAxon
hydrogen acceptor count 5 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 103.35 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 72.96 ChemAxon
polarizability 26.44 ChemAxon
药物相互作用
Drug Interaction
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.
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.
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.
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.
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.
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.
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.
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.
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.
Triprolidine The CNS depressants, Triprolidine and Tolcapone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
食物相互作用
Not Available

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