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

Abstract

ABSTRACT:Induction of drug-metabolizing enzymes (DMEs) is highly speciesspecific 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.

Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

“…Gender-related differences in drug metabolism, especially in the rat, have been reported for numerous drugs and occur in both phase I and phase II metabolism (Gradolatto et al, 2005;Anari et al, 2006;Prakash et al, 2007aPrakash et al, ,b, 2008. One factor commonly known to contribute to gender-and species-dependent metabolism is differential expression of drug metabolism enzymes, especially cytochrome P450 isoforms (Martignoni et al, 2006;Richert et al, 2008). In this study, several novel and unusual oxidative metabolites (M4, M5, M14, M16, M19, M24, and M26) and ribose conjugates (M8, M9a, M9b, M9c, M12, M115a, M15b, and M15c), formed by multiple pathways (N-dealkylation, oxidation, glucosylation, and ribosylation), were identified.…”

Transcriptomic Hepatotoxicity Signature of Chlorpromazine after Short- and Long-Term Exposure in Primary Human Sandwich Cultures

“…Microarray analysis has great utility for the elucidation of underlying mechanisms of hepatotoxicity (Richert et al, 2008;Lauer et al, 2009). …”

Cell-Based Screening: Extracting Meaning from Complex Data

“…Humans and mice diverged in evolution over 65 million years ago, and many publications show that results from mice fail to reliably predict results from humans in drug absorption, distribution, metabolism, elimination, toxicity, bioavailability, carcinogenicity, teratogenicity, and efficacy as well as disease pathophysiology. Known differences in pharmacodynamics (Richert et al, 2008; Xie et al, 2000) and toxicology (Carlson et al, 2009; Singh and Gupta, 1985) between humans and non-human models could affect drug safety. Differences exist in physiological responses and drug effects in human cells (e.g., neurons), compared to murine or other non-human counterparts (Berger et al, 2006; Castan et al, 1994; Curtis et al, 1997; Derian et al, 1995; Guo et al, 1989; Keshavaprasad et al, 2005; Kopin et al, 1997; Liang et al, 2010; Mattson et al, 1991; Okazaki et al, 1995; Penhoat et al, 1996; Rasakham and Liu-Chen, 2011).…”