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The Liver Toxicity Biomarker Study: Phase I Design and Preliminary Results
1 BG Medicine, Inc., Waltham, MA, USA Correspondence: Robert Nicholas McBurney, 610 N. Lincoln St., Waltham, MA 02451; e-mail:rmcburney{at}bg-medicine.com. 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.
Key Words: liver toxicity • biomarker • entacapone • tolcapone Abbreviations: ALT, alanine aminotransferase • ANOVA, analysis of variance • AST, aspartate aminotransferase • CRADA, cooperative research and development agreement • CV, coefficient of variation • DTT, dithiothreitol • DFTMP, 1,1-difluoro-1-trimethylsilanyl methyl phosphanic acid • DILI, drug-induced liver injury • DNA, deoxyribonucleic acid • EH, high-dose, entacapone-treated cohort • EL, low-dose, entacapone-treated cohort • EM, medium-dose, entacapone-treated cohort • FDA, U.S. Food and Drug Administration • FT-MS, fourier transform mass spectrometer or spectrometry • FWHM, full width at half maximum • HPLC, high-performance liquid chromatography • LC/MS, liquid chromatography coupled to mass spectrometry • LTBS, The Liver Toxicity Biomarker Study • MALDI, matrix-assisted laser desorption ionization • MIAME, Minimal Information About a Microarray Experiment • MS, mass spectrometer or mass spectrometry • MS/MS, tandem mass spectrometry • NMR, nuclear magnetic resonance • PBS, phosphate-buffered saline • PCA, principal components analysis • QC, quality control • RIN, RNA integrity number • RNA, ribonucleic acid • RNAse, ribonuclease • RT, retention time • SCX, strong cation exchange • TEAB, tetraethylammonium bicarbonate • TFA, trifluoroacetic acid • TCEP, tris(2-carboxyethyl)phosphine • TH, high-dose, tolcapone-treated cohort • TL, low-dose, tolcapone-treated cohort • TM, medium-dose, tolcapone-treated cohort • ToF, time of flight • V, vehicle-treated cohort
This version was published on January
1, 2009 Toxicologic Pathology, Vol. 37, No. 1,
52-64 (2009) This article has been cited by other articles:
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