Summary
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).
Hence, COMT inhibition was much more effective in increasing endogenous plasma DOPA and DOPEG than in increasing the plasma concentrations of infused DOPA and DOPEG, suggesting that endogenously formed DOPA and DOPEG are more extensively metabolized by COMT than infused DOPA and DOPEG. Moreover, as the increase in the plasma half-lives of DOPA and DOPEG induced by COMT inhibition was mainly due to an increase in the volume of distribution, it can be concluded that the action of COMT limits the distribution of infused DOPA and DOPEG within the body.
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References
Acquas E, Carboni E, de Ree RHA, Da Prada M, Di Chiara G (1992) Extracellular concentrations of dopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methyltransferase inhibitor Ro 40–7592. J Neurochem 59:326–330
Assicot M, Bohuon C (1971) Presence of two distinct catechol-O-methyltransferase activities in red blood cells. Biochimie 53:871–874
Axelrod J (1966) Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol Rev 18:95–113
Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233:702–705
Borgulya J, Bruderer H, Bernauer K, Zürcher G, Da Prada M (1989) Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: synthesis and structure-activity studies. Helv Chim Acta 72:952–968
Chiueh CC, Kopin IJ (1978) Centrally mediated release by cocaine of endogenous epinephrine and norepinephrine from the sympathoadrenal medullary system of unanesthetized rats. J Pharmacol Exp Ther 205:148–154
Eisenhofer G, Goldstein DS, Kopin IJ (1989) Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal re-uptake in the sympathetic nervous system in vivo. Clin Sci 76:171–182
Friedgen B (1992) Effect of catechol-O-methyltransferase (COMT) inhibition on the in-vivo kinetics of dihydroxyphenylglycol (DOPEG), 3-methoxy-4-hydroxyphenylglycol (MOPEG) and dihydroxyphenylalanine (DOPA). Naunyn-Schmiedeberg's Arch Pharmacol 345 [Suppl]:R 103
Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27:135–206
Halbrügge T, Ungell A-L, Wölfel R, Graefe K-H (1988) Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 338:361–367
Halbrügge T, Lütsch K, Thyen A, Graefe K-H (1991) Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 344:720–727
Halbrügge T, Friedgen B, Ludwig J, Graefe KH (1993) Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 347:163–171
Henseling M, Eckert E, Trendelenburg U (1976) The distribution of 3H-(±)-noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes. Naunyn-Schmiedeberg's Arch Pharmacol 292:205–217
Kopin IJ (1972) Metabolic degradation of catecholamines. The relative importance of different pathways under physiological conditions and after administration of drugs. In: Blaschke, H, Muscholl E (eds) Catecholamines, Handbook Exp Pharmacol (vol XXXIII). Springer, Berlin Heidelberg New York, pp 270–282
Kopin IJ (1985) Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev 37:125–129
Männistö PT, Kaakkola S (1989) New selective COMT inhibitors: useful adjuncts for Parkinson's disease? TIPS 10:54–56
Männistö PT, Tuomainen P, Tuominen RK (1992) Different in vivo properties of three new inhibitors of catechol-O-methyltransferase in the rat. Br J Pharmacol 105:569–574
Nissinen E (1984) The site of O-methylation by membrane-bound catechol-O-methyltransferase. Biochem Pharmacol 33:3105–3108
Rivett AJ, Eddy BJ, Roth JA (1982) Contribution of sulfate conjugation, deamination, and O-methylation to metabolism of dopamine and norepinephrine in human brain. J Neurochem 39:1009–1016
Rowland M, Tozer TN (1989) Clinical pharmacokinetics: concepts and applications. Lea & Febiger, Philadelphia London, pp 308–311
Sachs L (1984) Angewandte Statistik (6th edn). Springer, Berlin Heidelberg New York Tokyo
Zürcher G, Keller HH, Kettler R, Borgulya J, Bonetti EP, Eigenmann R, Da Prada M (1990a) Ro 40–7592, a novel, very potent, and orally active inhibitor of catechol-O-methyltransferase: a pharmacological study in rats. Adv Neural 53:497–503
Zürcher G, Colzi A, Da Prada M (1990b) Ro 40–7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm [Suppl]32:375–380
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This study was supported by the Deutsche Forschungsgemeinschaft (GR 490/5). A preliminary account of the results was presented to the German Society for Pharmacology and Toxicology (Friedgen 1992)
Correspondence to K.-H. Graefe at the above address
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Friedgen, B., Halbrügge, T. & Graefe, KH. The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 347, 155–161 (1993). https://doi.org/10.1007/BF00169261
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DOI: https://doi.org/10.1007/BF00169261