The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers.
Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h.
Entacapone showed linear pharmacokinetics over the dose range studied: Cmax and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a tmax ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t1/2α of 0.27–0.37 h and t1/2β of 1.59–3.44 h.
Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen.
The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.
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Ball P, Knuppen R, Breuer H (1971) Purification and properties of catechol-O-methyltransferase of human liver. Eur J Biochem 21: 517–525
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
Bäckström R, Honkanen E, Pippuri A, Kairisalo P, Pystynen J, Heinola K, Nissinen E, Lindén I-B, Männistö PT, Kaakkola S, Pohto P (1989) Synthesis of some novel potent and selective catechol-O-methyltransferase (COMT) inhibitors. J Med Chem 32: 841–846
Calne DB, Reid JL, Vakil SD (1972) Parkinsonism treated with 3-O-methyldopa. Clin Pharmacol Ther 14: 386–389
Gancher ST, Nutt JG, Woodward WR (1987) Peripheral pharmacokinetics of levodopa in untreated, stable and fluctuating patients. Neurology 37: 940–944
Gervas J, Muradas B, Bazan E, Aguado E, de Yebenes J (1983) Effects of 3-OM-dopa on monoamine metabolism in rat brain. Neurology 33: 278–282
Guldberg HC, Marsden CA (1975) Catechol-O-methyltransferase: Pharmacological aspects and physiological role. Pharmacol Rev 27: 135–206
Kaakkola S, Wurtman R (1993) Effects of catechol-O-methyltransferase inhibitors and 1–3, 4-dihydroxyphenylalanine with or without carbidopa on extracellular dopamine in rat striatum. J Neurochem 60: 137–144
Karlsson M, Wikberg T (1992) Liquid chromatographic determination of a new catechol-O-methyltransferase inhibitor, entacapone, and its Z-isomer in human plasma and urine. J Pharm Biomed Anal 10: 593–600
Keränen T, Gordin A, Harjola V-P, Karlsson M, Korpela K, Pentikäinen PJ, Rita H, Seppälä L, Wikberg T (1993) The effect of catechol-O-methyltransferase inhibition by entacapone, on the pharmacokinetics and metabolism of levodopa in healthy volunteers. Clin Neuropharmacol 16: 145–156
Loo JCK, Riegelman S (1970) Assessment of pharmacokinetic constants from postinfusion blood curves obtained after iv infusion. J Pharm Sci 59: 53–55
Markwell MAK, Haas SM, Bieber LL, Tolbert NE (1978) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87: 206–210
Metzler CM, Weiner DL (1989) PCNONLIN Version 30 Software for the statistical analysis of nonlinear models on micros, PCNONLIN user guide. Statistical Consultants Inc, Lexington, Ky
Männistö PT, Kaakkola S (1990) Rationale for selective COMT inhibitors as adjuncts in the drug treatment of Parkinson's disease. Pharmacol Toxicol 66: 317–323
Männistö PT, Ulmanen I, Lundström K, Taskinen J, Tenhunen J, Tilgmann C, Kaakkola S (1992) Characteristics of catechol-O-methyltransferase (COMT) and properties of selective COMT-inhibitors. Prog in Drug Res 39: 291–350
Myllylä VV, Sotaniemi KA, Illi A, Suominen K, Keränen T (1993) Effects of entacapone, a COMT inhibitor, on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson's disease. Eur J Clin Pharmacol 45: 419–423
Nissinen E, Tuominen R, Perhoniemi V, Kaakkola S (1988) Catechol-O-methyltransferase in human and rat small intestine. Life Sci 42: 2609–2614
Nissinen E, Lindén I-B, Schultz E, Photo P (1992) Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone. Naunyn Schmiedeberg's Arch Pharmacol 346: 262–266
Nutt JG, Woodward WR, Gancher ST, Merrick D (1987) 3-O-methyldopa and the response to levodopa in Parkinson's disease. Ann Neurol 21: 584–588
Nutt JG, Woodward WR, Stone CK, Beckner RM, Carter JH, Gancher ST, Hammerstad JP, Gordin A (1994) Effects of peripheral catechol-O-methyltransferase (COMT) inhibitor on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients. Neurology (in press)
Reches A, Fahn S (1982) 3-O-methyldopa blocks dopa metabolism in rat corpus striatum. Ann Neurol 12: 267–271
Reches A, Miekle L, Fahn S (1982) 3-O-methyldopa inhibits rotations induced by levodopa in rats after unilateral destruction of the nigrostriatal pathway. Neurology 32: 887–888
Ruottinen H, Rinne UK (1993) Effect of COMT inhibition with entacapone on clinical response, pharmacokinetics and metabolism of levodopa in Parkinson's disease. Neurology 43 [Suppl 2]: 685
Schultz E, Nissinen E, Kaakkola S (1989) Determination of catechol-O-methyltransferase activity in erythrocytes by high performance liquid chromatography with electrochemical detection. Biomed Chromatogr 3: 64–67
Schultz E, Tarpila S, Bäckström A-C, Gordin A, Nissinen E, Pohto P (1991) Inhibition of human erythrocyte and gastroduodenal catechol-O-methyltransferase activity by nitecapone. Eur J Clin Pharmacol 40: 577–580
Törnwall M, Männistö PT (1993) Effects of three types of catechol O-methylation inhibitors on 1–3,4-dihydroxyphenylalanine-induced circling behaviour in rats. Eur J Pharmacol 250: 77–84
Wade L, Katzman R (1975) 3-O-methyldopa inhibition of L-dopa at the blood-brain barrier. Life Sci 17: 131–136
Waldmeier PC, Baumann PA, Feldtrauer JJ, Hauser K, Bittiger H, Bischoff S, Von Sprecher G (1990) CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure. Naunyn-Schmiedeberg's Arch Pharmacol 342: 305–311
Weinshilboum RM (1978) Human erythrocyte catechol-O-methyltransferase: correlation with lung and kidney activity. Life Sci 22: 625–630
Wikberg T, Vuorela A, Ottoila P, Taskinen J (1993) Identification of major metabolites of the catechol-O-methyltransferase inhibitor entacapone in the rat and in humans. Drug Metab Dispos 21: 81–92
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Keränen, T., Gordin, A., Karlsson, M. et al. Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone. Eur J Clin Pharmacol 46, 151–157 (1994). https://doi.org/10.1007/BF00199880
- healthy volunteers
- adverse effects