| 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 |
|
| 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 |
|
| Toxicity |
LD50 = 1600 mg/kg (Orally in rats) |
