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By K K Jain MD

The chemical name of tolcapone is 3,4-Dihydroxy-4'-methyl-5-nitrobenzophenone. Pharmacology of tolcapone has been reviewed in more detail elsewhere (Truong 2009).

Mechanism of action. Tolcapone inhibits the action of the enzyme catechol-O-methyltransferase, which acts to metabolize or degrade catechols that include dopamine, adrenaline, and noradrenaline. Catechol-O-methyltransferase, found in the synaptic cleft of dopaminergic neurons, is the second most significant metabolic pathway for levodopa. O-methylation reactions may influence the response to levodopa in Parkinson disease by the following mechanisms:

  • Catechol-O-methyltransferase in the gut may metabolize levodopa during absorption and, thus, reduce the bioavailability of the drug.
  • O-methylation of levodopa in the systemic circulation can facilitate the elimination of levodopa from plasma and, thus, reduce the plasma half-life of levodopa.
  • O-methylation of levodopa by catechol-O-methyltransferase in the brain capillary endothelial cells further reduces the entry of levodopa into the brain.
  • O-methylation of dopamine terminates the action of the neurotransmitter in the brain.

Accumulation of O-methylated levodopa in the brain was initially considered to inhibit levodopa transport to the brain. Studies with PET show that 3-O-methyldopa does not inhibit the transport of levodopa analog 18F-dopa into the brain. However, catechol-O-methyltransferase inhibition, which successfully blocks O-methylation, is a useful strategy to increase the bioavailability of levodopa. Catechol-O-methyltransferase inhibitors substantially increase the levels of free 18F-dopa in the plasma and the striatum after their administration. Free striatal 18F-dopa storage increases following catechol-O-methyltransferase administration in patients with early Parkinson disease, but there is only a small increase in patients with advanced disease. Therefore, it is likely that in advanced Parkinson disease the benefits of catechol-O-methyltransferase inhibition are likely due to the maintenance of plasma levodopa levels rather than the provision of a greater striatal store of levodopa available for decarboxylation. Further 18F-dopa PET studies have shown that tolcapone has a significant blocking effect on peripheral and central catechol-O-methyltransferase but not dopa decarboxylase activity.

Tolcapone lowers elevated homocysteine levels associated with levodopa treatment in patients with Parkinson disease (Müller and Kuhn 2006). This may reduce long-term degenerative changes in the brain associated with hyperhomocysteinemia.

Pharmacokinetics. Tolcapone is rapidly absorbed when given orally and is rapidly eliminated with a mean half-life of approximately 2 hours. Tolcapone is metabolized to 3-O-methyl-tolcapone, which has an elimination half-life of approximately 30 hours. Bioavailability of tolcapone is 60% following oral administration due to first pass metabolism. Tolcapone is almost completely metabolized and excreted in urine and feces; glucuronidation is the most important route of metabolism. No accumulation of tolcapone or its metabolite occurred when multiple doses of the drug were given to elderly volunteers.

Pharmacodynamics. In healthy volunteers, 200 mg doses of tolcapone produces a significant reduction in erythrocyte catechol-O-methyltransferase activity with maximum inhibition at 2 hours that returns to baseline levels within 24 hours. Tolcapone significantly increases the levodopa and dopamine concentrations (80% and 92% respectively) in patients with Parkinson disease and reduces 3-O-methyldopa levels by 80% when given at a dose of 200 mg 3 times daily along with levodopa/carbidopa. Clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics and excludes any central effects of tolcapone on dopa decarboxylase.

Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and markedly inhibits ATP synthesis in cultured cells (Korlipara et al 2004). This action may be relevant to its effect on liver function, but its toxicity may also involve a mechanism independent of its effects on oxidative phosphorylation.

A controlled study using fMRI revealed that tolcapone improves cognition and cortical information processing in normal human subjects (Apud et al 2007). Individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone.