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Species Differences in the Response of Liver Drug-Metabolizing Enzymes to (S)-4-O-Tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric Acid (EMD 392949) in Vivo and in Vitro

Laboratoire de Biologie Cellulaire, l'Institut Fédératif de Recherches 133, Facultéde Médecine et de Pharmacie, Besançon, France (L.R., A.B.); KaLy-Cell, Temis Innovation, Besançon, France (L.R., C.V.-A., N.B.); Merck KGaA, Merck Serono, Non-Clinical Development, Toxicology, Darmstadt, Germany (G.T., S.O.M.); Merck KGaA, Merck Serono, Non-Clinical Development, Drug Metabolism and Pharmacokinetics, Grafing, Germany (E.W., H.D.); Service de Chirurgie Viscérale et Digestive—Centre de Transplantation Hépatique, Hôpital Jean Minjoz, Besançon, France (B.H.); and Service de Chirurgie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (N.H.)

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) / 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 PPAR 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 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 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 PPAR agonists in monkeys and humans.