TY - JOUR
T1 - The complete pharmacokinetic profile of serum cardiac troponin I in the rat and the dog
AU - Dunn, Michael E.
AU - Coluccio, Denise
AU - Hirkaler, Gerard
AU - Mikaelian, Igor
AU - Nicklaus, Rosemary
AU - Lipshultz, Steven E.
AU - Doessegger, Lucette
AU - Reddy, Micaela
AU - Singer, Thomas
AU - Geng, Wanping
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/10
Y1 - 2011/10
N2 - Recent improvements in assays have allowed serum cardiac troponin I (cTnI) to be measured at previously undetectable concentrations, which may have implications for cardiotoxicity studies. We characterized the pharmacokinetics of cTnI after a single iv administration of purified cTnI in rats at doses of 0.005, 0.05, and 0.5 μg/kg and in beagle dogs at doses of 0.05, 0.1, and 0.2 μg/kg. Serum cTnI concentration-time profiles were well described by a two-compartment pharmacokinetic model with first-order elimination in both species. The estimated mean (SD) values of total serum clearance, volume of distribution of the central compartment, and terminal half-life were 318 ml/h/kg, 52.9 ml/kg, and 0.8 h in rats and 481 (135) ml/h/kg, 230 (70) ml/kg, and 1.85 (0.5) h in dogs, respectively. In both species, a fast distribution phase was followed by a relatively slow elimination phase. These data indicate that the current practice in cardiotoxicity studies of unguided blood sampling should be revised. A targeted case-by-case approach is required whereby samples are collected not only relative to the kinetics of the test article but also in relation to the kinetics of the biomarker in the test species and the type and severity of anticipated cardiovascular perturbation. This approach is essential for the identification of subtle increases of serum cTnI concentrations in the low dynamic range.
AB - Recent improvements in assays have allowed serum cardiac troponin I (cTnI) to be measured at previously undetectable concentrations, which may have implications for cardiotoxicity studies. We characterized the pharmacokinetics of cTnI after a single iv administration of purified cTnI in rats at doses of 0.005, 0.05, and 0.5 μg/kg and in beagle dogs at doses of 0.05, 0.1, and 0.2 μg/kg. Serum cTnI concentration-time profiles were well described by a two-compartment pharmacokinetic model with first-order elimination in both species. The estimated mean (SD) values of total serum clearance, volume of distribution of the central compartment, and terminal half-life were 318 ml/h/kg, 52.9 ml/kg, and 0.8 h in rats and 481 (135) ml/h/kg, 230 (70) ml/kg, and 1.85 (0.5) h in dogs, respectively. In both species, a fast distribution phase was followed by a relatively slow elimination phase. These data indicate that the current practice in cardiotoxicity studies of unguided blood sampling should be revised. A targeted case-by-case approach is required whereby samples are collected not only relative to the kinetics of the test article but also in relation to the kinetics of the biomarker in the test species and the type and severity of anticipated cardiovascular perturbation. This approach is essential for the identification of subtle increases of serum cTnI concentrations in the low dynamic range.
KW - Biomarker
KW - Cardiac troponin I
KW - Dog
KW - Kinetics
KW - Rat
KW - Ultrasensitive assay
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U2 - 10.1093/toxsci/kfr190
DO - 10.1093/toxsci/kfr190
M3 - Article
C2 - 21775726
AN - SCOPUS:80053449638
VL - 123
SP - 368
EP - 373
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -