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Catechol-O-Methyltransferase Inhibitors in Parkinson’s Disease

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Abstract

Inhibitors of catechol-O-methyltransferase (COMT) are commonly used as an adjunct to levodopa in patients with Parkinson’s disease (PD) for the amelioration of wearing-off symptoms. This narrative review aims to discuss the role of COMT inhibitors on peripheral levodopa metabolism and continuous brain delivery of levodopa, and to describe their metabolic properties. Oral application of levodopa formulations with a dopa decarboxylase inhibitor (DDI) results in fluctuating levodopa plasma concentrations, predominantly due to the short half-life of levodopa and its slowing of gastric emptying. Following transport across the blood–brain barrier and its metabolic conversion to dopamine, these peripheral ‘ups and downs’ of levodopa are reflected in fluctuating dopamine levels in the synaptic cleft between presynaptic and postsynaptic dopaminergic neurons of the nigrostriatal system. As a result, pulsatile postsynaptic dopaminergic stimulation takes place and results in the occurrence of motor complications, such as wearing-off and dyskinesia. More continuous plasma behaviour was observed after the combination of levodopa/DDI formulations with COMT inhibitors. These compounds also weaken a levodopa/DDI-related homocysteine increase, as biomarker for an impaired methylation capacity, which is involved in an elevated oxidative stress exposure. These findings favour the concept of chronic levodopa/DDI application with concomitant inhibition of COMT and monoamine oxidase, since deamination of dopamine via this enzyme also generates free radicals. This triple combination is suggested as standard levodopa application in patients with PD who need levodopa, if they will tolerate it.

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Disclosures

Professor Dr. Thomas Müller has performed studies, served on advisory boards and held lectures for Roche, Novartis, Orion and MEDA in the past 20 years. This manuscript was not funded by any of these companies.

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    Thomas Müller

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Müller, T. Catechol-O-Methyltransferase Inhibitors in Parkinson’s Disease. Drugs 75, 157–174 (2015). https://doi.org/10.1007/s40265-014-0343-0

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