COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise.
We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and catecholamine metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased 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 significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Illi
A
A
Orion-Farmos Pharmaceuticals, Orion Research Center, Espoo, Finland.
Sundberg
S
S
Koulu
M
M
Scheinin
M
M
Heinävaara
S
S
Gordin
A
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000328:Adult; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines / Q000097:blood*; D002396:Catechols / Q000008:administration & dosage* / Q000009:adverse effects; D002851:Chromatography, High Pressure Liquid; D004562:Electrocardiography; D005080:Exercise Test; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood; D009570:Nitriles; D012016:Reference Values
D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines; D002396:Catechols; D009570:Nitriles; D015102:3,4-Dihydroxyphenylacetic Acid; C071192:entacapone; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol