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Cited by 190Parkinson's Disease Mechanisms and TreatmentsDeep Brain Stimulation and Movement DisordersNeurotransmitter Receptor Influence on Behavior

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Catechol-O-Methyltransferase Inhibitors in Parkinson’s Disease

Müller, Thomas·2015·Drugs
DOI 10.1007/s40265-014-0343-0
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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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  • PD patients develop motor fluctuations of the wearing-off type with continued levodopa use due to increased drug breakdown by peripheral COMT, such as in the gut.

    “For example, PD patients develop motor fluctuations of the wearing-off type with continued levodopa use due to increased drug breakdown by peripheral COMT, such as in the gut–COMT inhibitors are a useful adjuvant therapy in PD and increase the time for which levodopa improves clinical symptoms [153].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [153]

  • COMT inhibitors are a useful adjuvant therapy in PD and increase the time for which levodopa improves clinical symptoms.

    “COMT inhibitors are a useful adjuvant therapy in PD and increase the time for which levodopa improves clinical symptoms [153].”

    From The gut–brain axis in early Parkinson’s disease: from prodrome to prevention (2025) · cites this paper as [153]

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Metadata

Authors
Müller, T.
Affiliations
St. Joseph-Krankenhaus (DE)
Corresponding author
Müller, Thomas
ORCID
Müller, Thomas
Venue
Drugs
Publisher
Springer Science and Business Media LLC
Published
2015-01-06
Volume
75
Issue
2
Pages
157-174
ISSN
  • 0012-6667 (ISSN-L)
  • 1179-1950
DOI
10.1007/s40265-014-0343-0
OpenAlex
W2003760823
Cited by
190
References
1
Citations by year
2026: 12 · 2025: 17 · 2024: 21 · 2023: 21 · 2022: 20 · 2021: 15 · 2020: 17 · 2019: 15 · 2018: 14 · 2017: 14 · 2016: 16 · 2015: 8
FWCI
2.28
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Drugs (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
catechol-O-methyltransferase inhibitors, Parkinson's disease, levodopa, dopa decarboxylase inhibitors, wearing-off phenomenon, dyskinesia, levodopa metabolism, homocysteine, oxidative stress, monoamine oxidase inhibitors, dopamine signaling
MeSH terms
Catechol O-Methyltransferase, Humans, Parkinson Disease, Structure-Activity Relationship, Catechol O-Methyltransferase Inhibitors

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