Tolcapone, is a medication used to treat Parkinson’s disease (PD).
A selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT).
Brand name Tasmar.
It has demonstrated significant liver toxicity.
Pregnancy category AU: B3
Routes of administration by mouth
Bioavailability 65%
Protein binding >99.9%
Metabolism Liver, mainly by glucuronidation
Elimination half-life 2–3 hours
Excretion Urine (60%), feces (40%)
Only 0.5% in unmetabolized form
Entacapone is another nitrocatechol COMT inhibitor: tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate the blood–brain barrier, acting both in the central nervous system and in the periphery.
It is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications.
With tolcapone, the beneficial effects of levodopa tend to wear off more slowly.
Contraindicated with non-selective monoamine oxidase inhibitors, with liver diseases or increased liver enzymes.
It has demonstrated significant liver hepatotoxicity. that limits its usefulness.
Minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored.
Ot may increase in dopaminergic activity, including digestive symptoms.
Has the risk of eliciting or prolonging dyskinesia, as it results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms.
Adverse reactions: nausea and diarrhea, dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness.
Urine discoloration comes from yellow metabolites being excreted in the urine.
Increased of dopamine levels is a desired interaction.
It can also increase the levels of other drugs metabolized by COMT: carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline.
It selectively and reversibly binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS).
It prevents the 3-O-methylation of levodopa by COMT in the periphery.
More of the levodopa that is administered reaches the CNS.
It improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS.
It is absorbed from the gut to about 85%.
It has an absolute bioavailability of 65%.
Its peak blood plasma concentrations after about two hours.
It is 99.9% bound to plasma proteins, primarily albumin.
Inactivation os primarily by glucuronidation.
Other mechanisms are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction/acetylation.
The half-life of tolcapone is two to three hours.
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.
99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4.
It penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity.
The U.S. Food and Drug Administration (FDA) issued a black box warning for liver disease.
Tolcapone approved for treatment of Parkinson disease and has Orphan Drug designation for treatment of ATTR.