Pharmacokinetics, disposition, and metabolism of [14C]-nebicapone in humans.
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 [(14)C]-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-O-nebicapone-glucuronide (BIA 3-476) identified as the major metabolite. Plasma concentration-time profiles of [(14)C]-nebicapone demonstrated T(max) (h) 1.25+/-0.65, t(1/2) (h) 134.55+/-25.67, C(max) (ng-eq/g) 19647.02+/-4930.20, AUC(0-t) (h.ng-eq/g) 161735.51+/-9224.66, AUC(0-infinity) (h.ng-eq/g) 199603.30+/-16854.08, and for whole blood T(max) 1.00+/-0.41, t(1/2) 32.98+/-22.82, AUC(0-t) 35539.23+/-13664.87, AUC(0-infinity) 36970.64+/-14559.17. Plasma pharmacokinetics of nebicapone demonstrated T(max) (h) 1.00+/-0.41, t(1/2) (h) 2.34+/-0.51; C(max) (ng-eq/g) 12650.00+/-2898.85, AUC(0-t) (h.ng-eq/g) 18719.96+/-734.18, AUC(0-infinity) (h.ng-eq/g) 18392.12+/-753.81; BIA 3-476 demonstrated T(max) 1.25+/-0.50, t(1/2) 3.47+/-0.68; C(max) 15250+/-2563.20, AUC(0-t) 53810.61+/-7358.81, AUC(0-infinity) 54541.21+/-7135.70; 3-O-methyl-nebicapone (BIA 3-270) demonstrated T(max) 21.01+/-6.01, t(1/2) 103.43+/-6.01; C(max) 286.25+/-20.48, AUC(0-t) 27641.89+/-4569.99, AUC(0-infinity) 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.
Wright
Lyndon C
LC
Department of Research & Development, BIAL, A Av. da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal.
Maia
Joana
J
Loureiro
Ana I
AI
Almeida
Luis
L
Soares-Da-Silva
Patrício
P
D000098:Acetophenones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000284:Administration, Oral; D001711:Biotransformation; D002250:Carbon Radioisotopes; D065098:Catechol O-Methyltransferase Inhibitors; D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008297:Male; D053719:Tandem Mass Spectrometry
D000098:Acetophenones; D002250:Carbon Radioisotopes; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; C433466:nebicapone