Mechanism of action of levodopa plus a peripheral dopa decarboxylase inhibitor

This illustration 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

DDC = dopa decarboxylase; DDI = dopa decarboxylase inhibitor; COMT = catechol-O-methyltransferase; 3-OMD = 3-O-methyldopa; MAO-A = monoamine oxidase type A; MAO-B = monoamine oxidase type B; DAT = dopamine transporter; DOPA = dihydroxyphenylalanine; DOPAC = 3,4-dihydroxyphenylacetic acid; HVA = homovanillic acid; D₁–D₅ = dopamine receptor subtypes 1–5.