Mechanism of action of levodopa plus a peripheral dopa decarboxylase inhibitor

The slide shows the mechanism of action of levodopa, when taken in combination with a dopa decarboxylase inhibitor (DDI). Levodopa can be metabolized to dopamine on either side of the blood–brain barrier.¹ It is therefore usually administered with a DDI and with a catechol-O-methyltransferase (COMT) inhibitor to prolong the peripheral levodopa half-life and to increase levodopa availability within the central nervous system.^2,3

After passing the blood–brain barrier, levodopa is metabolized by dopa decarboxylase (DDC, also known as aromatic L-amino acid decarboxylase) to dopamine, which is released into the synapse, where it binds to the dopamine receptors (D₁, D₂, D₃, D₄ and D₅) on post-synaptic neurons.¹ Dopamine is then cleared from the synapse either through reuptake into the dopamine neuron by the dopamine transporter (DAT),⁴ or catabolized by the mitochondrial monoamine oxidase (A or B) into metabolites such as DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid).⁵

References:
1. Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 2002; 41 (4): 261–309.

2. Hauser RA. Levodopa: Past, present, and future. Eur Neurol 2009; 62 (1): 1–8.

3. Jenner P, Rocha J-F, Ferreira JJ, et al. Redefining the strategy for the use of COMT inhibitors in Parkinson’s disease: the role of opicapone. Expert Rev Neurother 2021; 21 (9): 1019–1033.

4. Vaughan RA, Foster JD. Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci 2013; 34 (9): 489–496.

5. Masato A, Plotegher N, Boassa D, Bubacco L. Impaired dopamine metabolism in Parkinson’s disease pathogenesis. Mol Neurodegener 2019; 14 (1): 35.