Brands, Medical Use, Clinical Data
- Antiparkinson Agents
- Central Nervous System Agents
Brands / Synonyms
For the treatment of Parkinson's Disease
Tolcapone is a 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. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism 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.
rapidly absorbed (absolute bioavailability is about 65%)
LD50 = 1600 mg/kg (Orally in rats)
Biotrnasformation / Drug Metabolism
The main metabolic pathway of tolcapone is glucuronidation
TASMAR tablets are contraindicated in patients with liver disease, in patients who were withdrawn from TASMAR
because of evidence of TASMAR-induced hepatocellular injury or who have demonstrated hypersensitivity to the drug or
TASMAR is also contraindicated in patients with a history of non-traumatic rhabdomyolysis or hyperpyrexia and
confusion possibly related to medication .
Protein Binding: Although tolcapone is highly protein bound, in vitro studies have shown that
tolcapone at a concentration of 50 mg/mL did not displace other highly protein-bound drugs from their binding sites
at therapeutic concentrations. The experiments included warfarin (0.5 to 7.2 pg/mL), phenytoin (4.0 to 38.7 mg/mL),
tolbutamide (24.5 to 961 mg/mL) and digitoxin (9.0 to 27.0 mg/mL).
Drugs Metabolized by Catechol-O-Methyl transferase (COMT): Tolcapone may influence the
pharmacokinetics of drugs metabolized by COMT However, no effects were seen on the pharmacokinetics of the COMT
substrate carbidopa. The effect of tolcapone on the pharmacokinetics of other drugs of this class such as
a-methyldopa, dobutamine, apomorphine, and isoproterenol has not been evaluated. A dose reduction of such compounds
should be considered when they are coadministered with tolcapone.
Effect of Tolcapone on the Metabolism of Other Drugs: In vitro experiments have been
performed to assess the potential of tolcapone to interact with isoenzymes of cytochrome P450 (CYP). No relevant
interactions with substrates for CYP 2A6 (coumadin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine,
cyclosporine), CYP 2C19 (S- mephenytoin) and CYP 206 (desipramine) were observed in vitro. The absence of an
interaction with desipramine, a drug metabolized by cytochrome P450 2D6, was also confirmed in an in vivo
study where tolcapone did not change the pharmacokinetics of desipramine.
Due to its affinity to cytochrome P450 2C9 in vitro, tolcapone may interfere with drugs, whose clearance is
dependent on this metabolic pathway, such as tolbutamide and warfarin. However, in an in vivo interaction
study, tolcapone did not change the pharmacokinetics of tolbutamide. Therefore, clinically relevant interactions
involving cytochrome P450 2C9 appear unlikely. Similarly, tolcapone did not affect the pharmacokinetics of
desipramine, a drug metabolized by cytochrome P450 206, indicating that interactions with drugs metabolized by that
enzyme are unlikely. Since clinical information is limited regarding the combination of warfarin and tolcapone,
coagulation parameters should be monitored when these two drugs are coadministered.
Drugs That Increase Catecholamines: Tolcapone did not influence the effect of ephedrine, an indirect
sympathomimetic, on hemodynamic parameters or plasma catecholamine levels, either at rest or during exercise. Since
tolcapone did not alter the tolerability of ephedrine, these drugs can be coadministered.
When TASMAR was given together with levodopa/carbidopa and desipramine, there was no significant change in blood
pressure, pulse rate and plasma concentrations of desipramine. Overall, the frequency of adverse events increased
slightly. These adverse events were predictable based on the known adverse reactions to each of the three drugs
individually. Therefore, caution should be exercised when desipramine is administered to Parkinsonís disease
patients being treated with TASMAR and levodopa/carbidopa.
In clinical trials, patients receiving TASMAR/levodopa preparations reported a similar adverse event profile
independent of whether or not they were also concomitantly administered selegiline (a selective MAO-B inhibitor).