Current Topics in Medicinal Chemistry

Allen B. Reitz
Fox Chase Chemical Diversity Center, Inc.
Doylestown, PA


In Vitro Microsomal Hepatic Metabolism of Antiasthmatic Prototype LASSBio-448

Author(s): 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.

Graphical 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.

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Article Details

Page: [1388 - 1398]
Pages: 11
DOI: 10.2174/1568026614666140506123718