title: In vitro microsomal hepatic metabolism of antiasthmatic prototype LASSBio-448.
abstract: In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl- LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4-dimethoxyphenyl and 1,3- benzodioxole subunits, respectively, in agreement with the in silico prediction using MetaSite Program. The development of a reproducible analytical methodology for the major metabolites by using HPLC-MS showed that both reactions require NADPH generating system and appeared to be catalyzed by cytochrome P450 (CYP). The identification of which isoenzyme was involved in the oxidative metabolism of LASSBio-448 was carried out by pre-incubations with the selective inhibitors sulfaphenazole (CYP2C9), quinidine (CYP2D6), furafylline (CYP1A2), p-nitrophenol (CYP2E1), ticlopidine (CYP2C19) and ketoconazole (CYP3A4). CYP1A2, CYP2C19 and CYP3A4 were demonstrated to be involved in the oxidative biotransformation of LASSBio-448.
authors.forename: Isabelle Karine
authors.initials: IK
authors.lastname: Costa Nunes
authors.forename: Luzineide Wanderley
authors.initials: LW
authors.lastname: Tinoco
authors.forename: Helvecio
authors.initials: H
authors.lastname: Martins-Junior
authors.forename: Claudia
authors.initials: C
authors.lastname: Rezende
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude, Bloco B, sala 14, Rio de Janeiro, RJ, Brazil, 21941-971. lidia@lassbio.icb.ufrj.br.
authors.forename: Lidia Moreira
authors.initials: LM
authors.lastname: Lima
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D052117:Benzodioxoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018927:Anti-Asthmatic Agents; D052117:Benzodioxoles; C000595839:LASSBio-448; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System