The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit.
The present study, carried out in anaesthetized rabbits, aimed at determining the effects of catechol-O-methytransferase (COMT) inhibition on the plasma kinetics of infused 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylalanine (DOPA) as well as on endogenous plasma noradrenaline, DOPEG, DOPA and 3-methoxy-4-hydroxyphenylglycol (MOPEG). The plasma kinetics of infused MOPEG were also evaluated. To block the function of COMT, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) was given intravenously. Dose-finding experiments, in which the drug-induced fall in endogenous plasma MOPEG was used to quantify COMT inhibition, indicated that a Ro 40-7592 dose of 3 mg/kg followed by 1.5 mg/kg every 30 min was sufficient to obtain a virtually complete inhibition of COMT. More than 150 min of COMT inhibition were required for endogenous MOPEG to disappear from plasma, since the plasma half-life of MOPEG was 54 min. COMT inhibition produced marked increases in the plasma levels of endogenous DOPA (1.7-fold) and DOPEG (3.9-fold) and did not alter endogenous plasma noradrenaline. The results concerning the effect of COMT inhibition on the plasma kinetics of infused DOPA and DOPEG were as follows: the plasma clearance of DOPA was not altered, whereas that of DOPEG fell by 41%; the plasma half-life of DOPA increased from 4.9 to 13.0 min and that of DOPEG from 4.8 to 31.0 min; there was an increase in the volume of distribution of DOPA (2 to 3-fold) and DOPEG (4 to 5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
Friedgen
B
B
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Federal Republic of Germany.
Halbrügge
T
T
Graefe
K H
KH
D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000097:blood*; D065098:Catechol O-Methyltransferase Inhibitors; D004295:Dihydroxyphenylalanine / Q000097:blood* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009596:Nitrophenols; D009638:Norepinephrine / Q000097:blood; D011817:Rabbits; D000077867:Tolcapone
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D008734:Methoxyhydroxyphenylglycol; D004295:Dihydroxyphenylalanine; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine