Qualification of cardiac troponin I concentration in mouse serum using isoproterenol and implementation in pharmacology studies to accelerate drug development.
Cardiac troponin I is a useful biomarker of myocardial injury, but its use in mice and application to early drug discovery are not well described. The authors investigated the relationship between cTnI concentration in serum and histologic lesions in heart tissue from mice treated with isoproterenol (ISO). Cardiac TnI concentrations in serum increased in a dose-dependant manner and remained increased twenty-four to forty-eight hours after a single administration of isoproterenol. Increased cTnI concentration was of greater magnitude and longer duration than increased fatty acid binding protein 3 concentration, aspartate aminotransferase activity, and creatine kinase activity in serum. Isoproterenol-induced increases in cTnI concentrations were both greater and more sustained in BALB/c than in CD1 mice and correlated with incidence and severity of lesions observed in heart sections from both strains. In drug development studies in BALB/c mice with novel kinase inhibitors, cTnI concentration was a reliable stand-alone biomarker of cardiac injury and was used in combination with measurements of in vivo target inhibition to demonstrate an off-target contribution to cardiotoxicity. Additional attributes, including low cost and rapid turnaround time, made cTnI concentration in serum invaluable for detecting cardiotoxicity, exploring structure-activity relationships, and prioritizing development of compounds with improved safety profiles early in drug discovery.
Engle
Steven K
SK
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, USA. Englesk@lilly.com
Jordan
William H
WH
Pritt
Michael L
ML
Chiang
Alan Y
AY
Davis
Myrtle A
MA
Zimmermann
John L
JL
Rudmann
Daniel G
DG
Heinz-Taheny
Kathleen M
KM
Irizarry
Armando R
AR
Yamamoto
Yumi
Y
Mendel
David
D
Schultze
A Eric
AE
Cornwell
Paul D
PD
Watson
David E
DE
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002316:Cardiotonic Agents / Q000633:toxicity; D003402:Creatine Kinase / Q000037:antagonists & inhibitors / Q000097:blood; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins / Q000097:blood; D005260:Female; D006331:Heart Diseases / Q000097:blood* / Q000139:chemically induced*; D006352:Heart Ventricles / Q000187:drug effects; D006651:Histocytochemistry; D007249:Inflammation / Q000378:metabolism; D007545:Isoproterenol / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D019210:Troponin I / Q000097:blood*
D015415:Biomarkers; D002316:Cardiotonic Agents; C493409:Fabp3 protein, mouse; D000074026:Fatty Acid Binding Protein 3; D050556:Fatty Acid-Binding Proteins; D047428:Protein Kinase Inhibitors; D019210:Troponin I; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D007545:Isoproterenol