Pharmacokinetics and pharmacodynamics of levodopa/carbidopa cotherapies for Parkinson’s disease

ABSTRACT

Introduction: Parkinson’s disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug. Particularly, long-term application of oral levodopa/decarboxylase inhibitor formulations sooner or later supports onset of fluctuations of movement. It also shifts levodopa turnover to O-methylation, which impairs human methylation capacity and increases oxidative stress.

Areas covered: This narrative review summarizes pharmacokinetic and pharmacodynamic features of available levodopa cotherapies on the basis of a literature search with the terms L-dopa, inhibitors of catechol-O-methyltransferase and monoamine oxidase-B.

Expert opinion: Long-term levodopa/dopa decarboxylase inhibitor application with concomitant inhibition of both, catechol-O-methyltransferase and monoamine oxidase-B supports a more continuous dopamine substitution, which ameliorates fluctuations of motor behavior. This triple combination also enhances both, antioxidative defense and methylation capacity. Inhibition of monoamine oxidase-B reduces generation of oxidative stress in the brain. Constraint of catechol-O-methyltransferase reduces homocysteine synthesis due to diminished consumption of methyl groups for levodopa turnover at least in the periphery. An additional nutritional supplementation with methyl group donating and free radical scavenging vitamins is recommendable, when future drugs are developed for long-term levodopa/dopa decarboxylase treated patients. Personalized medicine treatment concepts shall also consider nutritional aspects of Parkinson’s disease.

KEYWORDS:

• Monoamine oxidase
• catechol-O-methyltransferase
• levodopa
• oxidative stress
• homocysteine

Article highlights

• Inhibitors of monoamine oxidase-B reduce central dopamine turnover and ameliorate motor behavior in patients with Parkinson’s disease.

• Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase B supports the concept of dopaminergic stimulation.

• Long-term L-dopa/dopa decarboxylase inhibitor application increases oxidative stress and homocysteine synthesis, both of which contribute to aging processes and chronic neurodegeneration.

• Central metabolism of biogenic amines via monoamine oxidase-B supports generation of oxidative stress and thus progression of Parkinson’s disease.

• Peripherally acting catechol-O-methyltransferase inhibitors as cotherapy during long-term levodopa/dopa decarboxylase inhibitor administration lessen increase of homocysteine increase, which is a biomarker of an impaired methylation capacity.

• Inhibition of catechol-O-methyltransferase and monoamine oxidase-B complement each other in terms of improvement of motor complications and metabolic long-term consequences of chronic L-dopa/dopa decarboxylase inhibitor application.

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Declaration of interest

T Müller Has received honoraria for lectures form Zambon. Bial and Orion in the past. The author has no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.