1. In Vitro Microsomal Hepatic Metabolism of Antiasthmatic Prototype LASSBio-448
- Author
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Luzineide W. Tinoco, Lídia Moreira Lima, Claudia M. Rezende, Helvecio Martins-Junior, Eliezer J. Barreiro, and Isabelle Karine da Costa Nunes
- Subjects
Male ,Furafylline ,Pharmacology ,Sulfaphenazole ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Drug Discovery ,medicine ,Animals ,Anti-Asthmatic Agents ,Benzodioxoles ,Rats, Wistar ,Biotransformation ,Sulfonamides ,Molecular Structure ,biology ,CYP3A4 ,Chemistry ,CYP1A2 ,Cytochrome P450 ,General Medicine ,CYP2E1 ,Rats ,Biochemistry ,Microsomes, Liver ,biology.protein ,Microsome ,Drug metabolism ,medicine.drug - 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.
- Published
- 2014
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