Pharmacokinetics, Disposition, and Metabolism of [14C]-Nebicapone in Humans

Lyndon      C. Wright; Joana      Maia; Ana      I. Loureiro; Luis      Almeida; Patricio      Soares-Da-Silva

doi:10.2174/187231210791698465

Abstract

Objective: This study investigated the absorption, distribution, metabolism and excretion (ADME) of nebicapone [BIA 3-202; 1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone], a reversible catechol-O-methyltransferase (COMT) inhibitor, in 4 healthy male subjects. Methods; This was a single center, open, non-placebo-controlled, single-group, and a single 200 mg dose study of [14C]-nebicapone (2.5 MBq). Blood, urine and faeces were collected up to 264 hours post-dose. Results: Collectively more than 22 metabolites were identified in plasma, urine and faeces, with 3-Onebicapone- glucuronide (BIA 3-476) identified as the major metabolite. Plasma concentration-time profiles of [14C]- nebicapone demonstrated Tmax (h) 1.25±0.65, t1/2 (h) 134.55±25.67, Cmax (ng-eq/g) 19647.02±4930.20, AUC0-t (h.ng-eq/g) 161735.51±9224.66, AUC0-∞ (h.ng-eq/g) 199603.30±16854.08, and for whole blood Tmax 1.00±0.41, t1/2 32.98±22.82, AUC0-t 35539.23±13664.87, AUC0-∞ 36970.64±14559.17. Plasma pharmacokinetics of nebicapone demonstrated Tmax (h) 1.00±0.41, t1/2 (h) 2.34±0.51; Cmax (ng-eq/g) 12650.00±2898.85, AUC0-t (h.ng-eq/g) 18719.96±734.18, AUC0-∞ (h.ngeq/ g) 18392.12±753.81; BIA 3-476 demonstrated Tmax 1.25±0.50, t1/2 3.47±0.68; Cmax 15250±2563.20, AUC0-t 53810.61 ±7358.81, AUC0-∞ 54541.21±7135.70; 3-O-methyl-nebicapone (BIA 3-270) demonstrated Tmax 21.01±6.01 , t1/2 103.43± 6.01; Cmax 286.25±20.48, AUC0-t 27641.89±4569.99, AUC0-∞ 36968.12±4294.42. Conclusions: Nebicapone and BIA 3- 476 accounted for most early phase circulating nebicapone-derived moieties, have limited circulating cell association, peak concentrations shortly after dosing, and short body residence. In longer terminal half-life phases low concentrations of BIA 3-270 predominate. While about 70% of the dose was eliminated in the urine as BIA 3-476, < 1% of the dose was excreted as unchanged nebicapone. Faecal excretion accounted for 17.3% administered dose. On average, the total recovery of 88.6% of the radioactivity suggested no worrisome retention of drug derived material following a single 200 mg administration of nebicapone to healthy volunteers. The treatment was very well tolerated with no reported adverse events.

Keywords: Catechol-O-methyltransferase, nebicapone, ADME, human, safety

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