Norepinephrine Metabolites in Plasma as Indicators of Pharmacological Inhibition of Monoamine Oxidase and Catechol O-Methyltransferase

Abstract

Publisher Summary This chapter reports the results from studies investigating the usefulness of plasma 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol(MHPG) concentrations as indicators of pharmacological inhibition of monoamine oxidase type A (MAO-A) and catechol O-methyltransferase (COMT) activity in vivo in human subjects. Such indicators are needed in the clinical development of new inhibitors of MAO and COMT. According to studies, the concentration of DHPG in plasma appears to be a sensitive and specific indicator of pharmacological inhibition of MAO-A activity. It is suggested that DHPG measurements could be used in early clinical studies to determine the dosage and dose interval of new inhibitors of MAO-A, especially because no equally simple and convenient alternatives are available. Whether DHPG responses could be used to monitor drug intake and dose requirements and/or to predict therapeutic efficacy in depressed patients receiving MAO-A inhibitors remains to be determined. Pharmacological inhibition of COMT is also accurately reflected in increased DHPG and decreased MHPG concentrations in plasma. Inhibition of COMT was studied both in resting subjects and in combination with marked stimulation of the sympathetic nervous system with submaximal bicycle exercise. In the studies inhibition of COMT by entacapone or nitecapone had no effects on the plasma concentrations of unconjugated NE and epinephrine, neither at rest nor during physical exercise, which elevated plasma NE approximately six-fold and epinephrine approximately 10-fold.