Since its demonstration of effectiveness against Parkinson disease in 1961, levodopa has become the mainstay therapy for this disease. However, most orally administered levodopa is converted by catechol-O-methyltransferase into the inactive metabolite 3-O-methyldopa before crossing the blood-brain barrier. The accumulated 3-O-methyldopa then competes with levodopa for the saturable neutral amino acid active transport system in the gut and blood vessel wall, leading to motor fluctuations. The purpose of catechol-O-methyltransferase inhibitors such as entacapone and tolcapone is to inhibit the action of this enzyme.
Catechol-O-methyltransferase is widely distributed in human tissues including glia (Guldberg and Marsden 1975). Catechol-O-methyltransferase inhibition lowers the circulating levels of 3-O-methyldopa and improves the bioavailability of levodopa. The first-generation, nonselective catechol-O-methyltransferase inhibiting drugs were studied in the 1970s but were abandoned because of toxicity and lack of efficacy. The second-generation catechol-O-methyltransferase inhibitors, which were developed in the late 1980s, are reversible catechol-O-methyltransferase inhibitors and are in clinical trials. Two compounds of this category have been developed, entacapone and tolcapone. The United States Food and Drug Administration approved tolcapone in 1998 and entacapone in 1999. Due to reports of hepatotoxicity, its use was suspended in the European Union and is restricted by a warning in the United States. Tolcapone, however, remains an option in patients with fluctuating Parkinson disease who are receiving levodopa and are not responding to or tolerating other adjunctive treatments. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring (Unger et al 2008).