Pharmacodynamics. Entacapone inhibits catechol-O-methyltransferase in a dose-dependent, reversible, and tight-binding manner but does not affect other catechol metabolizing enzymes. It enables the reduction of levodopa dose. Catechol-O-methyltransferase inhibitors may influence the response to levodopa in Parkinson disease by the following mechanisms:
Catechol-O-methyltransferase inhibitors substantially increase the levels of free 18F-dopa in the plasma and the striatum after their administration. Catechol-O-methyltransferase inhibitors act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time. Repeated dosing of entacapone inhibits the catechol-O-methyltransferase activity in a dose-dependent manner and thereby reduces the loss of levodopa to 3-O-methyldopa, leading to improvement in the patients' clinical condition. Results of a single-blind, randomized, cross-over study confirm the ability of entacapone to enhance the clinical efficacy of controlled-release levodopa formulations and provide further evidence that entacapone is of value in extending the benefits of levodopa in Parkinson disease patients experiencing motor fluctuations (Stocchi et al 2004). Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation by 25% when administered concomitantly with a controlled-release levodopa preparation (Paija et al 2005).
Peripherally acting entacapone, unlike the centrally acting tolcapone, is a safer catechol-O-methyltransferase inhibitor for the treatment of Parkinson disease because it does not interfere with mitochondrial energy metabolism at pharmacologically effective concentrations. Entacapone administration as an adjunct produces a greater reduction in homocysteine in levodopa-induced hyperhomocysteinemia when associated with low folate levels in patients with Parkinson disease (Zesiewicz et al 2006).
Pharmacokinetics. Important pharmacokinetic features of entacapone include:
A high-performance liquid chromatography method with ultraviolet light is used for the quantification of entacapone in human plasma (Ramakrishna et al 2005). It is considered to be a sensitive, reproducible, and simple method for use in pharmacokinetic studies.