Toxicology and safety of COMT inhibitors.

The development of catechol-O-methyltransferase (COMT) inhibitors for the adjunct treatment to levodopa and aromatic L-amino acid decarboxylase (AADC) inhibitors in Parkinson's disease started in the late 1950s. The first-generation inhibitors were associated with toxic properties: they induced convulsions, or they were toxic to the liver. None of them was taken into clinical use. The second-generation inhibitors entacapone and tolcapone have now been in clinical use for over a decade, and some new inhibitors are under development. The main adverse events in the use of entacapone and tolcapone are dopaminergic and dependent of the concomitant use of levodopa, but the symptoms are generally moderate or mild. Among the non-dopaminergic adverse events, diarrhea is the most prominent one induced by both entacapone and tolcapone. In clinical use, entacapone has been safe, but tolcapone is under strict regulations on liver enzyme monitoring, since in the early years, a few hepatotoxicity cases appeared, three of them with fatal outcome. The mechanism behind tolcapone-induced liver toxicity has been evaluated both in vitro and in vivo, but no clear answer exists at the moment. In the regulatory animal studies, both inhibitors have been safe with no reported toxicity. Also nebicapone, the latest of the second-generation inhibitors in clinical trials has shown some liver enzyme elevations in human subjects. New inhibitors with a structure differing from nitrocatechols are under development. No safety concerns have been reported connected to COMT inhibiton as such. COMT knockout mice are fertile without any pathologies due to the total COMT inhibition.