Entacapone

Pharmacology
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By K K Jain MD

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 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.

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:

  • Entacapone is rapidly absorbed after oral administration, and mean maximum plasma concentrations of 1160 to 1500 µg are reached within 0.7 to 1.3 hours after a single dose of 200 mg in patients with Parkinson disease.
  • Half-life of oral entacapone is 1 to 2 hours.
  • The Z-isomer of entacapone is the main metabolite in human plasma. The Z-isomer is approximately 5% of the total area under the curve of both isomers.
  • Systemic bioavailability is approximately 36% following an oral dose of 200 mg in healthy volunteers.
  • About 10% of the oral dose of entacapone is excreted in the urine within 8 hours.
  • Entacapone, in combination with levodopa or dopa decarboxylase inhibitor, increases the area under the curve of levodopa, which leads to less fluctuation of levodopa plasma concentrations.

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.