title: The liver toxicity biomarker study: phase I design and preliminary results.
abstract: 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.
authors.affiliation: BG Medicine, Inc., Waltham, MA 02451, USA. rmcburney@bg-medicine.com
authors.forename: Robert N
authors.initials: RN
authors.lastname: McBurney
authors.forename: Wade M
authors.initials: WM
authors.lastname: Hines
authors.forename: Linda S
authors.initials: LS
authors.lastname: Von Tungeln
authors.forename: Laura K
authors.initials: LK
authors.lastname: Schnackenberg
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Moland
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: James C
authors.initials: JC
authors.lastname: Fuscoe
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Su
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Fan
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.forename: Shelagh A
authors.initials: SA
authors.lastname: Booth
authors.forename: Raji
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Paul L
authors.initials: PL
authors.lastname: Courchesne
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Campbell
authors.forename: Armin
authors.initials: A
authors.lastname: Graber
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Juhasz
authors.forename: Tricin Y
authors.initials: TY
authors.lastname: Li
authors.forename: Moira D
authors.initials: MD
authors.lastname: Lynch
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Morel
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Plasterer
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Takach
authors.forename: Chenhui
authors.initials: C
authors.lastname: Zeng
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001577:Benzophenones / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism*; D002396:Catechols / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D009570:Nitriles / Q000633:toxicity*; D009596:Nitrophenols / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077867:Tolcapone
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D015415:Biomarkers; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone