CYP Reaction Phenotyping For Imrecoxib And Gliclazide, And Induction Study Of TD-0232

Recombinant CYP enzymes and pooled human liver microsomes were carried as powerful tools to phenotype P450 reaction for imrecoxib and gliclazide, meanwhile, the induction for rat liver CYPs was explored in vivo. The models of drug metabolism in vitro and the inducing model in rats in vivo were established.1. Investigation on the hydroxylation metabolism of imrecoxib in vitro by recombinant human CYPs.Imrecoxib, a new anti-inflammatory developed, was incubated with heterologous expression human cytochrome P450 (rCYPs) in vitro, to identify the drug-metabolizing enzymes involved in the hydroxylation of imrecoxib. Parent drug and metabolites were detected with liquid chromatography-multistage mass spectrometry, and the contribution of four CYPs in the hydroxylation metabolism of imrecoxib was evaluated by the rate of with total normalized rate (TNR) method. Imrecoxib is metabolized by CYP2C9, CYP2D6 and CYP3A4, which with the rate of as following: 62.5%, 21.1% and 16.4% respectively. CYP2C9 is the major enzyme involved in imrecoxib hydroxylation metabolism.2. The investigation on the drug-metabolizing enzyme of gliclazide in vitro.The aim of this study was to clarify the identity of the human cytochromes P450 (CYP) involved in its metabolism, and to investigate the difference between the in vitro and in vivo conditions. The metabolism of gliclazide was examined with human liver microsomes (HLM) and cDNA-expressed CYPs. The kinetic parameters of metabolite formation were calculated for HLM and competent isoforms. Individual contribution of P450 isoforms in gliclazide hydroxylation...