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Qualification of Cardiac Troponin I Concentration in Mouse Serum Using Isoproterenol and Implementation in Pharmacology Studies to Accelerate Drug Development

¹ Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana, 46285, USA
² National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA
³ Vet Path Services, Inc., Mason, Ohio, 45040, USA

Correspondence: Address correspondence to: Steven K. Engle or David E. Watson, Lilly Corporate Center, Indianapolis, IN 46285, USA; phone: 317-655-2121 or 317-433-2155; e-mail:Englesk{at}lilly.com orDavewatson{at}lilly.com.

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.

Key Words: troponin • biomarker • cardiac • necrosis • drug development • mouse

Abbreviations: AST, aspartate aminotransferase (also known as serum glutamic oxaloacetic transaminase) • CK, creatine kinase • CMC, carboxymethylcellulose • cTnC, cardiac troponin calcium binding subunit • cTnI, cardiac troponin inhibitory subunit (Tnni3) • cTnT, cardiac troponin tropomyosin binding subunit (Tnnt2) • CV, coefficient of variation • Fabp3, fatty acid binding protein 3 • GenBank, Protein symbols shown in parentheses. • ISO, isoproterenol • IVTI, in vivo target inhibition • LLQ, lower limit of quantitation • sc, subcutaneous • ULQ, upper limit of quantitation

This version was published on August 1, 2009

Toxicologic Pathology, Vol. 37, No. 5, 617-628 (2009)
DOI: 10.1177/0192623309339502


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