Catechol-O-methyltransferase (COMT) is one of the main enzymes responsible for the metabolism of levodopa, dopamine, other catecholamines (adrenaline and noradrenaline), and their metabolites. COMT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the hydroxyl group of catecholamines. COMT is widely distributed throughout the body including central nervous system neurons and glia, but not nigrostriatal dopamine neurons.
Levodopa is metabolized by several different enzymes, with dopa decarboxylase and COMT being most important. When levodopa is administered with a peripheral dopa decarboxylase inhibitor such as carbidopa or benserazide, COMT metabolism of levodopa predominates. COMT metabolizes levodopa to 3-O-methyldopa (3-OMD), a compound which may decrease levodopa absorption and efficacy. Peripherally acting COMT inhibitors block COMT in the gut and periphery. By decreasing levodopa metabolism, they make more levodopa available for transport across the blood-brain barrier over a longer time and also reduce 3-OMD production. When COMT inhibitors are added to levodopa therapy, striatal dopamine concentrations increase. Central COMT inhibition might further increase striatal dopaniine concentration by inhibiting the metabolism of dopamine to homovanillic acid (HVA).
Examples of COMT Inhibitors are:
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