title: Entacapone increases levodopa exposure and reduces plasma levodopa variability when used with Sinemet CR.
abstract: Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.
authors.affiliation: Clinical Research Services Turku, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Paija
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Eeva-Riitta
authors.initials: ER
authors.lastname: Kultalahti
authors.forename: Mika
authors.initials: M
authors.lastname: Leinonen
authors.forename: Risto
authors.initials: R
authors.lastname: Huupponen
authors.forename: Ariel
authors.initials: A
authors.lastname: Gordin
authors.forename: Kari
authors.initials: K
authors.lastname: Reinikainen
mesh_terms: D000328:Adult; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002230:Carbidopa / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000009:adverse effects* / Q000627:therapeutic use; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007980:Levodopa / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D009570:Nitriles; D010300:Parkinson Disease / Q000097:blood* / Q000188:drug therapy
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D009570:Nitriles; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; C071192:entacapone; D002230:Carbidopa