Catechol O-Methyltransferase Inhibition and the Treatment of Parkinson's Disease

Abstract

Publisher Summary Catechol O-methyltransferase (COMT) plays an important role in the metabolism of the dopamine precursor, l -dopa, and of dopamine. Inhibitors of COMT could alter the metabolism of L-dopa and dopamine to therapeutic advantage by a number of mechanisms in L-dopa-treated patients with Parkinson's disease (PD). The introduction of entacapone and tolcapone, reversible inhibitors of COMT that are well absorbed and well tolerated, has permitted investigation of the clinical importance of COMT in Parkinson's disease. Entacapone is primarily a peripheral inhibitor of COMT; tolcapone penetrates the blood brain barrier and inhibits brain COMT as well as peripheral COMT. This chapter discusses l -dopa absorption. COMT is in high concentration in the gut and liver and may contribute to first-pass metabolism of levodopa. Inhibition of gut and liver COMT would then be expected to increase the bioavailability of orally administered l -dopa. Pharmacokinetically, this should be manifest by an increase in peak concentration of plasma l -dopa and a decrease in the time-to-peak concentration. Neither entacapone nor tolcapone increases the peak concentration of levodopa or shortens the time-to-peak concentration in subjects with PD. These results are in contrast to the effect of inhibition of first-pass decarboxylation of l -dopa; the aromatic amino acid decarboxylase inhibitors, carbidopa and benserazide, markedly increase the peak plasma L-dopa concentrations. These observations argue that first-pass O-methylation of l -dopa is not quantitatively important. To the extent that dyskinesia and, perhaps, some mental effects are related to peak concentrations of l -dopa, this lack of effect on peak concentrations by COMT inhibitors may be beneficial. The chapter also discusses L-dopa elimination, Antiparkinsonian effects of COMT inhibition, l -dopa transport into brain and inhibition of brain COMT. Potential benefit of inhibition of brain COMT is sparing of S- adenosylmethionine, the methyl donor for O-methylation reactions. Low cerebrospinal fluid S-adenosylmethionine concentrations have been linked to depression and dementia.