DOPA Alone

Other evaluated serological markers from the melanogenesis pathway include the phaeomelanin metabohte S-S-CD (see Ref. 5 for an review of 5-S-CD in melanoma with 2648 samples taken from 218 patients) and to a lesser extent the eumelanin metabohte 6-hydroxy-5-methoxyindole-2-carboxyhc acid. Since 5-S-CD is very sensitive to light and oxidation, analysis requires immediate centrifugation, freezing of the samples after blood collection and exclusion of light and air-oxygen. 

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Since L-tyrosine is the main precursor of melanins and a substrate of tyrosinase, the L-DOPA/L-tyrosine ratio could more accurately reflect tyrosinase activity than l-DOPA alone. In 1997, we developed two reversed-phase HPLC techniques, one with electrochemical detection to measure simultaneously l-DOPA, norepinephrine (NE), epinephrine (E), dopamine (DA), and DOPAC (3,4-dihydroxyphenyl acetic acid) (all compounds easily oxidizable between +0.15 and +0.50 V), and one with fluorimetric detection to measure L-tyrosine (and phenylalanine) on the same blood sample. 

Figure 15.4 The central and peripheral metabolism of levodopa and its modification by drugs, (a) Levodopa alone. After oral administration alone most dopa is rapidly decarboxylated to DA in the gut and blood with some o-methylated (COMT) to o-methyl/dopa (OMD). Only a small amount (3%) enters the CNS to be converted to DA. (b) After an extracerebral dopa decarboxylase inhibitor. Blocking just the peripheral dopa decarboxylase (DD) with inhibitors like carbidopa and benserazide, that cannot enter the CNS (extra cerebral dopa decarboxylase inhibitors, ExCDDIs), stops the conversion of levodopa to DA peripherally, so that more enters the CNS or is o-methylated peripherally to OMD.

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Starr MS (1995) Antiparkinsonian actions of glutamate antagonists—alone and with l-dopa a review of evidence and suggestions for possible mechanisms. J Nemal Transm Park Dis Dement Sect 10 141-185... 

In clinical practice, L-dopa is conventionally administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase (e.g., carbidopa). If L-dopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites. Inhibition of peripheral decarboxylase by carbidopa markedly increases the fraction of orally administered L-dopa that remains unmetabolized and available to enter the brain (i.e., its bioavailability). 

Brannan T, Yahr MD (1995) Comparative study of selegiline plus L-dopa-carbidopa versus L-dopa-carbidopa alone in the treatment of Parkinson s disease. Ann Neurol 37 95-98. 

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