A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran.
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.
Safety Assessment, Molecular Toxicology, AstraZeneca R&D, Södertälje, Sweden. ulf.s.andersson@astrazeneca.com
Ulf
U
Andersson
Johan
J
Lindberg
Shunghuang
S
Wang
Raji
R
Balasubramanian
Maritha
M
Marcusson-Ståhl
Mira
M
Hannula
Chenhui
C
Zeng
Peter J
PJ
Juhasz
Johan
J
Kolmert
Jonas
J
Bäckström
Lars
L
Nord
Kerstin
K
Nilsson
Steve
S
Martin
Björn
B
Glinghammar
Karin
K
Cederbrant
Ina
I
Schuppe-Koistinen
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood*; D001384:Azetidines / Q000009:adverse effects*; D001596:Benzylamines / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis*; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002986:Clinical Trials as Topic; D050716:Complement C4b-Binding Protein; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000097:blood; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D055432:Metabolomics / Q000379:methods; D017293:Protein S; D040901:Proteomics / Q000379:methods; D019289:Pyruvic Acid / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000097:blood; D049490:Systems Biology; D014407:Tumor Cells, Cultured; D014809:Vitamin D-Binding Protein / Q000097:blood
D001384:Azetidines; D001596:Benzylamines; D015415:Biomarkers; D001798:Blood Proteins; C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D006649:Histocompatibility Antigens; C523390:PROS1 protein, human; D017293:Protein S; D014809:Vitamin D-Binding Protein; C426686:ximelagatran; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D000410:Alanine Transaminase; D016186:Receptor, Macrophage Colony-Stimulating Factor