The liver toxicity biomarker study: phase I design and preliminary results.
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.
McBurney
Robert N
RN
BG Medicine, Inc., Waltham, MA 02451, USA. rmcburney@bg-medicine.com
Hines
Wade M
WM
Von Tungeln
Linda S
LS
Schnackenberg
Laura K
LK
Beger
Richard D
RD
Moland
Carrie L
CL
Han
Tao
T
Fuscoe
James C
JC
Chang
Ching-Wei
CW
Chen
James J
JJ
Su
Zhenqiang
Z
Fan
Xiao-Hui
XH
Tong
Weida
W
Booth
Shelagh A
SA
Balasubramanian
Raji
R
Courchesne
Paul L
PL
Campbell
Jennifer M
JM
Graber
Armin
A
Guo
Yu
Y
Juhasz
Peter J
PJ
Li
Tricin Y
TY
Lynch
Moira D
MD
Morel
Nicole M
NM
Plasterer
Thomas N
TN
Takach
Edward J
EJ
Zeng
Chenhui
C
Beland
Frederick A
FA
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
D000978:Antiparkinson Agents; D001577:Benzophenones; D015415:Biomarkers; D002396:Catechols; D009570:Nitriles; D009596:Nitrophenols; C071192:entacapone; D000077867:Tolcapone