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| Trade names | Tasmar |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a698036 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 65% |
| Protein binding | >99.9% |
| Metabolism | Liver (mainly glucuronidation) |
| Eliminationhalf-life | 2–3 hours |
| Excretion | Urine (60%), feces (40%); only 0.5% in unmetabolized form |
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| ECHA InfoCard | 100.222.604 |
| Chemical and physical data | |
| Formula | C14H11NO5 |
| Molar mass | 273.244 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 143 to 146 °C (289 to 295 °F) |
| Solubility in water | not soluble |
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Tolcapone, sold under the brand nameTasmar, is a medication used to treatParkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of theenzymecatechol-O-methyltransferase (COMT).[4] It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
Tolcapone appears to beperipherally selective, but can still cross into the brain in significant amounts and has been found to inhibit COMT centrally as well[clarification needed].[5][6] In comparison withentacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate into the brain, acting both in thecentral nervous system and in the periphery.[7] However, entacapone is less toxic for the liver.
Tolcapone is used in the treatment of Parkinson's disease as an adjunct tolevodopa/carbidopa or levodopa/benserazide medications.Levodopa is aprodrug fordopamine, which reduces Parkinson symptoms;carbidopa and benserazide arearomaticL-amino acid decarboxylase (AADC) inhibitors.[8]
Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations.[9]
Combining tolcapone with non-selectivemonoamine oxidase inhibitors such asphenelzine ortranylcypromine is contraindicated.[10] Tolcapone is also contraindicated for people with liver diseases or increasedliver enzymes.[11]
Tolcapone has demonstrated significantliver toxicity (hepatotoxicity)[12] that limits the drug's utility.Entacapone is an alternative, largely since it has a more favorable toxicity profile.
The hepatotoxicity can be related to elevated levels oftransaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormalmitochondrial respiration due to the uncoupling ofoxidative phosphorylation.[13]
Other side effects regard the increase in dopaminergic activity, including digestive symptoms.[11] Treatment with tolcapone runs the risk of eliciting or prolongingdyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donorS-adenosyl-L-methionine (SAM) in thestriatum that induces Parkinson symptoms.[13]
Digestive symptoms includenausea anddiarrhea; further dopaminergic side effects includeorthostatic hypotension, dry mouth, sweating and dizziness. Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies.[10] Urine discoloration comes from yellow tolcaponemetabolites being excreted in the urine and is harmless.[11][13]
While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benserazide, as well asmethyldopa,dobutamine,apomorphine,epinephrine (adrenaline), andisoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increasecatecholamine concentrations, such as monoamine oxidase (MAO) inhibitors andnorepinephrine reuptake inhibitors; these also showed only slight effects in practice. Combination withnon-selective MAO inhibitors might be dangerous.[10][11]
Due to its affinity to the liver enzymeCYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction withtolbutamide, a 2C9substrate, was observed in studies.[11]
Tolcapone selectively and reversibly[10] binds to thecatalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the threecatecholamines, including levodopa.[15] It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross theblood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS.[16]
The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as thedissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg).[17]
Tolcapone is quickly absorbed from the gut to about 85%. It has an absolutebioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound toplasma proteins, primarilyalbumin. The main inactivation step isglucuronidation; other processes are methylation by COMT, hydroxylation byCYP3A4 andCYP2A6 with subsequent oxidation to acarboxylic acid, and possibly a minor path with reduction to an amine with subsequentacetylation.[10][11]
The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person).[9] 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine.[10][11]
99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols,nitecapone andentacapone, because it has higherlipophilicity due to its R-substituent.[vague] Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively. Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier.[18]
Tolcapone has been said to enter thecentral nervous system only minimally and hence would appear to beperipherally selective.[5] However, tolcapone is morelipophilic than other COMT inhibitors likeentacapone and may be more likely to cross theblood–brain barrier (BBB).[6] A imaging study in humans found that tolcapone also inhibited COMT in the brain to a significant degree.[6]
Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic,crystalline compound with a relativemolecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1 M aqueous sodium hydroxide solution. ThepKa values are 4.5 and 10.6 for the twophenyl groups; and the maximum absorption is at 268 nm (in 0.1 Mhydrochloric acid / ethanol).[10] Its chemical name is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone.
A synthesis of tolcapone proposed in 2008, begins with aGrignard reaction between 4-Benzyloxy-3-methoxybenzaldehyde[19][20] andp-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodiumt-butoxide. The benzyl protecting group is removed bypalladium-catalyzedhydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol.[21]
Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications. Consequentially, the marketing authorization of tolcapone was suspended from December 1998 until August 2004 when it was lifted. In November 1998, the company that manufactured tolcapone voluntarily[22] removed the drug from the market. The authorization was then renewed in August 2009.[23]
As a result of reported complications, the USFood and Drug Administration (FDA) issued ablack box warning for tolcapone and label revisions that aimed to regulate the monitoring of those prescribed tolcapone for Parkinson's disease in November 1998.[24] A number of other countries withdrew tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998.[22]
Because of preliminary data suggesting the drug may have activity, the U.S. FDA in 2013 granted tolcapone "orphan drug status" in studies aiming at the treatment of transthyretinfamilial amyloidosis (ATTR).[25] However, as of 2015[update] tolcapone was not FDA approved for the treatment of this disease.[26]
Inanimal studies, tolcapone showsantidepressant- andanti-anhedonia-like effects, stimulatesexploratory behavior, and enhances thelocomotor hyperactivity induced bypsychostimulants likeamphetamine andnomifensine.[27][28][29] Tolcapone has beenclinically studied in the treatment of certainpsychiatric disorders such asobsessive–compulsive disorder (OCD).[30][31] There is also interest in brain-penetrant COMT inhibitors like tolcapone for the treatment ofschizophrenia[30][32] as well asdisorders of diminished motivation likeapathy.[33]
The efficacy of tolcapone as an adjunct to levodopa in patients with Parkinson's disease has primarily been attributed to its ability to inhibit peripheral it is thought that tolcapone enters the CNS to a minimal extent only.[16] However, results [17] of a study in patients with Parkinson's disease, as well as results of animal studies,[18-21] suggest that tolcapone also has central activity.
The possible central effect of tolcapone, which is more lipophilic than entacapone and may be more likely to cross the blood-brain barrier (BBB), has been under debate for many years.26 An (18)F-dopa positron emission tomography study showed its effect as a central COMT inhibitior.27 However, this effect was not translated into clinical benefit in L-dopa-naive patients, in whom tolcapone alone or added to selegiline was compared with placebo.28 Tolcapone is more efficacious than entacapone, as it reduces total OFF time by an average of 98 minutes daily.
It also enhances locomotor hyperactivity induced by amphetamine and nomifensine and stereotypy induced by amphetamine, and stimulates exploratory activity in the open field test in rats and mice.14 Tolcapone potentiates levodopa antagonism of haloperidol-induced catalepsy in MPP+-lesioned mice (murine model of Parkinson's disease) and potentiates and prolongs levodopa-induced circling behavior in rats with 6-hydroxydopamine-induced nigrostriatal pathway lesions (another animal model of Parkinson's disease).23, 24 [...] The effect of tolcapone on animal models of depression was evaluated in two studies. In rats with chronic mild stress-induced anhedonia, tolcapone 10 or 30 mg/kg twice/day by intraperitoneal injection prevented the stress-induced anhedonic state compared with vehicle-treated controls.28 Another rat study using the forced swimming test and learned helplessness paradigm, found no significant antidepressant activity of the agent.29 The relevance of these findings to the management of depression in humans with both parkinsonian and nonparkinsonian disease is unknown.
Tolcapone administered 6 h before amphetamine challenge was found to significantly increase locomotor activity in rats treated with 0.5 and 2.0 mg kg-1 amphetamine. In rats given 4.0 mg kg-1 amphetamine, tolcapone produced a marked decrease in locomotor activity and increased two-fold the duration of the stereotyped behaviour.
