ABSTRACT
Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity.
Subject(s)
Alanine Transaminase/blood , Azetidines/adverse effects , Benzylamines/adverse effects , Biomarkers/analysis , Chemical and Drug Induced Liver Injury/etiology , Adenosine Triphosphate/metabolism , Blood Proteins/metabolism , Cells, Cultured , Clinical Trials as Topic , Complement C4b-Binding Protein , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , Histocompatibility Antigens/blood , Humans , Macrophages/physiology , Male , Metabolomics/methods , Protein S , Proteomics/methods , Pyruvic Acid/metabolism , Receptor, Macrophage Colony-Stimulating Factor/blood , Systems Biology , Tumor Cells, Cultured , Vitamin D-Binding Protein/bloodABSTRACT
Drug-induced liver injury (DILI) is the primary adverse event that results in withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in development. The Liver Toxicity Biomarker Study (LTBS) is an innovative approach to investigate DILI because it compares molecular events produced in vivo by compound pairs that (a) are similar in structure and mechanism of action, (b) are associated with few or no signs of liver toxicity in preclinical studies, and (c) show marked differences in hepatotoxic potential. The LTBS is a collaborative preclinical research effort in molecular systems toxicology between the National Center for Toxicological Research and BG Medicine, Inc., and is supported by seven pharmaceutical companies and three technology providers. In phase I of the LTBS, entacapone and tolcapone were studied in rats to provide results and information that will form the foundation for the design and implementation of phase II. Molecular analysis of the rat liver and plasma samples combined with statistical analyses of the resulting datasets yielded marker analytes, illustrating the value of the broad-spectrum, molecular systems analysis approach to studying pharmacological or toxicological effects.