Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone

Abstract

Entacapone, OR-611, was found to be a potent peripherally acting inhibitor of catechol-O-methyltransferase (COMT). IC50 values of 10 nmol/l and 160 nmol/l were obtained for rat duodenum and liver-soluble COMT, respectively. There were no effects on other catecholamine metabolizing enzymes. Entacapone showed reversible, tight-binding type of inhibition of soluble rat liver COMT with a Ki-value of 14 nmol/l and it also caused 50% inhibition of rat duodenal, erythrocyte, liver and striatal COMT activity 1 h after oral dosing with 1.1, 5.4, 6.7 and 24.2 mg/kg, respectively. However, penetration of entacapone into the brain was poor, since the formation of homovanillic acid (HVA), the O-methyl metabolite of dopamine in the striatum, was not reduced, even after the highest dose of 30 mg/kg. In rat blood serum, the concentration of 3-O-methyldopa (3OMD), the O-methylated product of L-dopa, was reduced in a dose-dependent manner, and the concentration of L-dopa was increased after the administration of entacapone (3-30 mg/kg p.o.) together with L-dopa + carbidopa. These changes were reflected, in the striatum, by a significant rise in the dopamine concentration and a reduction in the 3OMD concentration. Consequently, when entacapone was added to the treatment with L-dopa + carbidopa, the dose of L-dopa could be lowered from 50 mg/kg to 15 mg/kg in order to produce the same striatal dopamine concentrations as with 50 + 50 mg/kg of L-dopa + carbidopa alone.

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

“…Furthermore, tolcapone inhibited striatal COMT more effectively than entacapone. Our results agree with previous animal results from COMT inhibitor studies suggesting that tolcapone penetrates into the brain, whereas entacapone has a mainly peripheral action (Zü rcher et al, 1991;Kaakkola and Wurtman, 1992;Mä nnistö et al, 1992;Nissinen et al, 1992;Copeland, 2000). Additionally, the ability of tolcapone (200 mg) to inhibit central COMT in humans has been demonstrated very recently using 18 F-dopa positron emission tomography (Ceravolo et al, 2002).…”

“…In our experiments, guided by this knowledge, entacapone and tolcapone had equal IC 50 values against rat liver total COMT but also against S-COMT and MB-COMT fractions. The K i values of entacapone and tolcapone in liver total COMT were equal and the same order of magnitude as previously reported in separate studies using rat liver COMT (Zü rcher et al, 1990a;Nissinen et al, 1992).…”

“…There have been several separate studies assessing the in vitro potency of entacapone or tolcapone and inhibition kinetics of COMT (Schultz and Nissinen, 1989;Zü rcher et al, 1990b;Nissinen et al, 1992;Borges et al, 1997;VieiraCoelho and Soares-Da-Silva, 1999), but only three groups have compared entacapone and tolcapone under equal experimental conditions. According to Learmonth et al (2002) tolcapone is more potent than entacapone both against rat brain and against liver COMT.…”

“…The time course of COMT activity in different tissues has been studied in experimental animals after oral administration of entacapone or tolcapone but at very different doses (Zü rcher et al, 1990b(Zü rcher et al, , 1991Nissinen et al, 1992). These previous results suggest that tolcapone generally has a longer duration of action, but the pharmacodynamic properties of entacapone and tolcapone have been compared generally only in one single-dose (30 mg/kg) study published during the preparation of this article (Learmonth et al, 2002).…”

“…These previous results suggest that tolcapone generally has a longer duration of action, but the pharmacodynamic properties of entacapone and tolcapone have been compared generally only in one single-dose (30 mg/kg) study published during the preparation of this article (Learmonth et al, 2002). On the basis of COMT inhibitor studies in experimental animals, it has been proposed that tolcapone penetrates to the brain, whereas entacapone has a mainly peripheral action (Zü rcher et al, 1991;Kaakkola and Wurtman, 1992;Mä nnistö et al, 1992;Nissinen et al, 1992), but to date, there are no numeric data based on actual drug concentrations.…”