title: 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.
authors.affiliation: Orion Farmos-Pharmaceuticals, Orion Research Center, Espoo, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Nissinen
authors.forename: I B
authors.initials: IB
authors.lastname: Lindén
authors.forename: E
authors.initials: E
authors.lastname: Schultz
authors.forename: P
authors.initials: P
authors.lastname: Pohto
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004386:Duodenum / Q000187:drug effects / Q000201:enzymology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009570:Nitriles; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; C071192:entacapone; D004295:Dihydroxyphenylalanine; C008404:3-methoxytyrosine; D004298:Dopamine; D006719:Homovanillic Acid