ISSX 2013 - CYP Induction Time Course

ISSX 2013 - CYP Induction Time Course

Published:  29 September 2013

Time-course of Cytochrome P450 (CYP450) induction in cultured human hepatocytes: Evaluation of activity and mRNA expression profiles for six inducible CYP450 enzymes 

Enzyme induction potential for new drug candidates is typically evaluated in vitro with cultured human hepatocytes with a demonstrated utility for the quantitative prediction of drug interactions involving cytochrome P450 (CYP450) enzymes, particularly CYP3A4.  Recently, many researchers have begun to measure CYP450 mRNA expression in vitro for prediction of clinical outcomes for CYP3A4 with relative success. Furthermore, recent regulatory guidance from the FDA and EMA now recommends CYP450 mRNA expression as the primary in vitro endpoint as opposed to CYP450 activity. 
 
The purpose of this study was to evaluate the time-course of CYP450 induction in cultured human hepatocytes to determine the adequate treatment period and establish CYP450 mRNA expression or enzymatic activity as reasonable endpoints for each of the six inducible hepatic CYP450 enzymes, namely CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4.