COMT INHIBITION BY HIGH-DOSE ENTACAPONE DOES NOT AFFECT HEMODYNAMICS BUT CHANGES CATECHOLAMINE METABOLISM IN HEALTHY-VOLUNTEERS AT REST ANDDURING EXERCISE

We studied the effects of catechol-O-methyltransferase (COMT) inhibiti on with entacapone on hemodynamics and catecholamine metabolism in hea lthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven heal thy male volunteers; on the first period 400 mg t.i.d. and on the seco nd 800 mg t.i.d. A submaximal exercise test giving a heart rate of abo ut 163-167 beats/min with the highest predetermined work load was perf ormed on a bicycle ergometer, and blood pressure, heart rate and ECG w ere recorded. The concentrations of adrenaline, noradrenaline, 3,4-dih ydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Bloo d pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and rep eated dosing of entacapone. The plasma concentrations of DHPG (a monoa mine oxidase (MAO)-dependent metabolite) increased maximally by 245% c ompared to the control day. DOPAC (a MAO-dependent metabolite) increas ed maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was si gnificantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemo dynamics or plasma concentrations of unconjugated adrenaline and norad renaline in healthy volunteers either at rest or during exercise. Howe ver, it changes the metabolism of endogenous catecholamines, with a di fferent behavior of DHPG and MHPG with respect to dosage and time of e xposure to entacapone.