Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone

Abstract

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.

Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

“…After oral administration, significantly higher plasma levels and a higher AUC value were attained with tolcapone than with entacapone, a reflection not only of the better bioavailability but also the slower elimination of tolcapone. These results are in parallel with human studies (Kerä nen et al, 1994;Jorga et al, 1998;Heikkinen et al, 2001).…”

“…Also, in single-dose (100 or 200 mg) human studies, tolcapone has a much longer duration of action than entacapone; the COMT activity of erythrocytes has fully recovered within 8 h after dosing entacapone, whereas after administration of tolcapone, the inhibition lasted for over 12 h (Kerä nen et al, 1994;Dingemanse et al, 1995). During repeated administration of entacapone (Rouru et al, 1999) or tolcapone (Dingemanse et al, 1996), no change was observed in their pharmacodynamics.…”

“…At therapeutic oral doses, both drugs are rapidly eliminated with an apparent t 1/2 of 1.6 to 3.4 h, but tolcapone generally has a longer duration of action as assessed by inhibition of COMT activity in erythrocytes (Kerä nen et al, 1994;Dingemanse et al, 1995). These apparent differences in the duration of action of entacapone and tolcapone have led to different treatment strategies; entacapone is recommended to be given with each dose of levodopa, whereas tolcapone is given three times a day in an attempt to keep COMT continuously inhibited (Mä nnistö and Kaakkola, 1999).…”

Human Metabolism of Nebicapone (BIA 3-202), a Novel Catechol-O-Methyltransferase Inhibitor: Characterization of in Vitro Glucuronidation

“…In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7%) are the predominant metabolites found (Jorga et al, 1999). Regarding entacapone, the only metabolite described in human plasma is the Zisomer (ϳ5%) (Wikberg et al, 1993;Keranen et al, 1994); however, in human urine, besides the Z-isomer (ϳ25%), the 3-O-␤-glucuronic acid derivative (ϳ70%) is the prevalent metabolite (Wikberg et al, 1993).…”

“…In urine, the 3-O-␤-glucuronic conjugates of tolcapone (ϳ13%) and its derivative N-acetyl amino (ϳ5.7%) are the predominant metabolites found (Jorga et al, 1999). Regarding entacapone, the only metabolite described in human plasma is the Zisomer (ϳ5%) (Wikberg et al, 1993;Keranen et al, 1994); however, in human urine, besides the Z-isomer (ϳ25%), the 3-O-␤-glucuronic acid derivative (ϳ70%) is the prevalent metabolite (Wikberg et al, 1993).No methylation products of entacapone were detected in human plasma or urine, possibly because the nitro group of entacapone hinders methylation of the catechol (Wikberg et al, 1993). As an alternative to molecular conjugation with endogenous species like glucuronidation, sulfation, methylation, glutathione conjugation, and acetylation (phase II drug metabolism reactions), these drugs could undergo oxidation, reduction, and hydroxylation (phase I drug metabolism reactions); however, such phase I metabolites are minor (Wikberg et al, 1993;Jorga et al, 1999).…”