title: Species differences in pharmacokinetic and pharmacodynamic properties of nebicapone.
abstract: The present study was designed to characterize pharmacodynamic and pharmacokinetic properties of nebicapone in rats and mice. Upon oral administration of nebicapone the extent of mouse liver catechol-O-methyltransferase (COMT) inhibition is half that in the rat. Nebicapone was rapidly absorbed reaching plasma C(max) within 30min and being completely eliminated by 8h. Nebicapone was metabolized mainly by glucuronidation and methylation in both species, but rat had an extra major metabolite, resulting from sulphation. Administration of nebicapone by the intraperitoneal route significantly increased compound AUC in the rat while in the mouse a significant increase in AUC of metabolites was observed. These results show that nebicapone exhibited marked species differences in bioavailability and metabolic profile. Evaluation of COMT activity in rat and mice liver homogenates revealed that both had similar methylation efficiencies (K(cat) values, respectively 7.3 and 6.4min(-1)), but rat had twice active enzyme units as the mouse (molar equivalency respectively 150 and 83). Furthermore, nebicapone inhibited rat liver COMT with a lower K(i) than mouse liver COMT (respectively 0.2nM vs. 1.2nM). In conclusion, the results from the present study show that mice and rats respond differently to COMT inhibition by nebicapone. The more pronounced inhibitory effects of nebicapone in the rat may be related to an enhanced oral availability and less pronounced metabolism of nebicapone in this specie, but also concerned with the predominant expression of S-COMT over MB-COMT, the latter of which is less sensitive to inhibition by nebicapone than the former.
authors.affiliation: Department of Research and Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bonifácio
authors.forename: Ana I
authors.initials: AI
authors.lastname: Loureiro
authors.forename: Leonel
authors.initials: L
authors.lastname: Torrão
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandes-Lopes
authors.forename: Lyndon
authors.initials: L
authors.lastname: Wright
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Pinho
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000042:Absorption; D000098:Acetophenones / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002394:Catechol O-Methyltransferase / Q000032:analysis / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism; D007263:Infusions, Parenteral; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013379:Substrate Specificity
chemical_list: D000098:Acetophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002394:Catechol O-Methyltransferase; C433466:nebicapone; D004837:Epinephrine