Received for publication August 17, 2007.
Revised January 7, 2008.
Accepted for publication January 22, 2008.

Species differences in the response of liver drug metabolizing enzymes to EMD 392949 in vivo and in vitro

Abstract

Induction of drug metabolizing enzymes (DMEs) is highly species-specific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species-specificity of the anti-diabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR)/ agonist EMD 392949 (EMD) with regards to the induction of gene expression and activities of DMEs, their regulators and typical PPAR target genes. EMD clearly induced PPAR target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (CYP) 4A. CYP2C and 3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of CYP activities as in monkeys, indicating that the monkey is predictive for human CYP induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPAR agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human CYP-induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible CYPs, with evidence of CYP3A and CYP2C inducibility by PPAR agonists in monkey and humans.

Key words: Ah receptor, CAR, CYP expression, CYP induction, human CYP enzymes, in vitro-in vivo prediction, nuclear receptors, PXR