RESUMO
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.
Assuntos
Alanina Transaminase/sangue , Azetidinas/efeitos adversos , Benzilaminas/efeitos adversos , Biomarcadores/análise , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Trifosfato de Adenosina/metabolismo , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Ensaios Clínicos como Assunto , Proteína de Ligação ao Complemento C4b , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Antígenos de Histocompatibilidade/sangue , Humanos , Macrófagos/fisiologia , Masculino , Metabolômica/métodos , Proteína S , Proteômica/métodos , Ácido Pirúvico/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/sangue , Biologia de Sistemas , Células Tumorais Cultivadas , Proteína de Ligação a Vitamina D/sangueRESUMO
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.