RT Journal Article
SR Electronic
T1 Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (<em>S</em>)-4-<em>O</em>-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 702
OP 714
DO 10.1124/dmd.107.018358
VO 36
IS 4
A1 Richert, Lysiane
A1 Tuschl, Gregor
A1 Viollon-Abadie, Catherine
A1 Blanchard, Nadège
A1 Bonet, Alexandre
A1 Heyd, Bruno
A1 Halkic, Nermin
A1 Wimmer, Elmar
A1 Dolgos, Hugues
A1 Mueller, Stefan O.
YR 2008
UL http://dmd.aspetjournals.org/content/36/4/702.abstract
AB 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 antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) α/γ agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPARα target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks 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 P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPARα 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 P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPARα agonists in monkeys and humans.