title: Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development.
abstract: We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow-up compound in a frontloaded 24-h single-dose acute study that was initiated before regular 2-week repeat-dose studies started. The high similarity of the follow-up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics-based early toxicity prediction in short-term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound-, animal-, and cost-intensive longer term studies are undertaken.
authors.affiliation: Pharma Research, F. Hoffmann-La Roche AG, Basel, Switzerland. adrian_b.roth@roche.com
authors.forename: Adrian
authors.initials: A
authors.lastname: Roth
authors.forename: Franziska
authors.initials: F
authors.lastname: Boess
authors.forename: Christian
authors.initials: C
authors.lastname: Landes
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.forename: Christian
authors.initials: C
authors.lastname: Freichel
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Plancher
authors.forename: Susanne
authors.initials: S
authors.lastname: Raab
authors.forename: Cristina
authors.initials: C
authors.lastname: de Vera Mudry
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiser
authors.forename: Laura
authors.initials: L
authors.lastname: Suter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D055808:Drug Discovery; D005786:Gene Expression Regulation; D023281:Genomics; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations / Q000032:analysis*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations; D002784:Cholesterol; D005978:Glutathione