The Toxicologist - Society of Toxicology

from 5 to 28 days in duration) in either rodent or non-rodents. The drugs assessed
belonged to different pharmacological classes, were of varying molecular weights,
had different routes of administration and were being developed for a variety of disease
indications. The incidence of cardiotoxicity (e.g. myocardial necrosis, myocarditis,
hypertrophy and myocardial degeneration) associated with a functional
perturbation was low (10%). Cardiotoxicity resulted when MABP decreased and
HR increased (63%) or with decreased HR alone (37%). There was no structural or
functional change in 46% of the drugs studied but interestingly, the remaining
44% had changes in at least 1 of the measured parameters but no histopathology.
There were no drugs that showed structural damage only. Taken together, these results
indicate that there is an association between the independent findings of functional
and structural change within the heart. This analysis also indicates that drugs
with no effect on HR, MABP or dP/dtmax in acute studies are likely to also show
no structural damage upon repeat dosing. Increasing our understanding of drugs
that cause functional change in the absence of structural change is critical in our
quest to reduce drug attrition due to cardiotoxicity.
202 USE OF NATRIURETIC PEPTIDES TO DETECT
COMPOUND RELATED CHANGES IN BLOOD
PRESSURE IN RODENTS.
S. K. Engle, L. Huber, D. Sall, M. Uhlik and D. E. Watson. Lilly Research
Laboratories, Eli Lilly and Company, Indianapolis, IN.
Cardiovascular toxicity is a serious adverse event observed in pre-clinical studies
during drug development. Myocardial degeneration is efficiently detected by markers
of membrane leakage, such as cardiac troponin I. In contrast, functional changes
in the cardiovascular (CV) system, such as blood pressure, are not easily detected in
rodent studies conducted in early drug development. Altered hemodynamic parameters
can, over time, lead to undesirable adaptations, such as cardiac hypertrophy, or
myocardial degeneration. Natriuretic peptides (NP), regulate blood pressure
through excretion of salt and water, and vasorelaxation, and are potential biomarkers
of change in blood pressure. We demonstrated the use of NPs in serum or
plasma as biomarkers of blood pressure changes in mice and rats. The direction of
change in blood pressure and NTproANP concentration were inversely related.
Treatment of mice with linifanib (25 mg/kg), a compound known to cause increased
mean arterial blood pressure (20-30 mmHG) in mice, caused a three-fold
decrease in NTproANP concentration (p