Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy

Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.