The inhibition of soluble catechol-O-methyl-transferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5-800 mg) and i.v. (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 t1/2 alpha of 0.27-0.37 h and t1/2 beta of 1.59-3.44 h. Over the dose range studied, the single oral and i.v. 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.

Metabolites of entacapone, (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl) propenamide, a potent inhibitor of catechol-O-methyltransferase, were isolated from dog urine. After hydrolysis of glucuronides and sulfates, 5 metabolites were identified in addition to unchanged entacapone by HPLC with diode-array UV detection, electron ionization mass spectrometry and IR spectroscopy. The (Z)-isomer of entacapone was the most abundant phase I metabolite while less abundant metabolites were formed through cleavage or reduction of the side chain carbon-carbon double bond, hydrolysis of the amide bond or through hydration of the nitrile group. The most abundant urinary metabolites were glucuronides. The glucuronidation site of these ortho-nitrocatechols was shown to be the hydroxyl meta to the nitro group.

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