In Vitro Microsomal Hepatic Metabolism of Antiasthmatic Prototype LASSBio-448
Isabelle Karine Costa Nunes, Luzineide Wanderley Tinoco, Helvecio Martins-Junior, Claudia Rezende, Eliezer J. Barreiro and Lidia Moreira Lima
Affiliation: Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude, Bloco B, sala 14, Rio de Janeiro, RJ, Brazil, 21941-971.
Keywords: Microsomes, metabolic stability, MetaSite, cytochrome P450 (CYP), LASSBio-448.
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.
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