Dopamine depletion, particularly in the striatum, is the neurochemical hallmark responsible for the motor features of PD. Levodopa, an aromatic amino acid and precursor to dopamine, readily crosses the blood-brain barrier (BBB) and to some extent normalizes dopamine levels. Two major enzymatic pathways for levodopa exist, leading to the formation of 3-O-methyldopa (3-OMD) peripherally and dopamine both peripherally and centrally. Dopamine is subsequently converted to 3,4-dioxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the CNS (Fig. 1).
When it is administered orally, levodopa is converted to dopamine in the extracerebral tissues via decarboxylation. To lessen the peripheral effects of dopamine and increase the brain bioavailability of levodopa, it is co-administered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors (AADIs). AADIs do not cross the BBB and, therefore, will not affect conversion to dopamine in the brain. Their use reduces the amount of levodopa required to attain an adequate response by approximately 75% and increases its plasma half-life from 50 to 90 min. The percent of levodopa entering the brain increases from ~3% to ~10%. The addition of a peripheral catechol-O-methyltransferase (COMT) inhibitor, enta-capone or tolcapone, prevents peripheral metabolism to 3-OMD and increases the half-life of levodopa (21).
Transport of levodopa across the gut mucosa and BBB involves an energy-dependent carrier-mediated system. Large neutral amino acids (LNAAs) compete for transport at the same sites. When oral levodopa is administered with a highprotein meal, there is an overall reduction in its plasma level. When IV levodopa is administered with a high-protein meal, the anticipated clinical response is
Levodopa > 3-OMD
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