ToxSci Advance Access originally published online on July 17, 2007
Toxicological Sciences 2007 99(2):637-648; doi:10.1093/toxsci/kfm184
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Published by Oxford University Press 2007.
The Utility of a Rodent Model in Detecting Pediatric Drug-Induced Nephrotoxicity
* Center for Drug Evaluation and Research, Silver Spring, Maryland 20993
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115
National Center for Toxicological Research, Jefferson, Arkansas 72079
1 To whom correspondence should be addressed at Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Life Sciences Laboratory Building 64, Room 2086, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Fax: (301) 796-9818. E-mail: parvaneh.espandiari{at}fda.hhs.gov.
Received April 18, 2007; accepted June 29, 2007
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Abstract |
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A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg–1 body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.
Key Words: gentamicin; age-related nephrotoxicity; biomarkers; Kim-1.
The contents of this paper do not necessarily reflect any position of the Government or the opinion of the Food and Drug Administration.
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