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The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity

Parvaneh Espandiari1, Jun Zhang, Barry A Rosenzweig

  • 1Center for Drug Evaluation and Research, Silver Spring, Maryland 20993, USA. parvaneh.espandiari@fda.hhs.gov

Toxicological Sciences : an Official Journal of the Society of Toxicology
|July 20, 2007
PubMed

Insights

Younger and older rats show increased kidney injury from gentamicin, while 25-day-old rats are more resistant. This multi-age model helps predict pediatric drug safety.

Area of Science:

  • Pharmacology
  • Toxicology
  • Developmental Biology

Background:

  • Gentamicin (GM) is an antibiotic with known nephrotoxicity.
  • Age-related differences in drug metabolism and toxicity are critical for pediatric drug safety.
  • Preclinical models are essential for evaluating drug safety across different life stages.

Purpose of the Study:

  • To investigate age-related differences in renal injury following gentamicin exposure in a multi-age rat model.
  • To identify specific developmental stages with increased susceptibility to gentamicin-induced nephrotoxicity.
  • To evaluate the utility of a multi-age animal model for predicting pediatric drug safety.

Main Methods:

  • Sprague-Dawley rats of 10, 25, 40, and 80 days old were administered gentamicin (0, 50, or 100 mg/kg/day) subcutaneously for 6 or 14 days.
  • Urine and serum samples were analyzed for biomarkers of kidney injury, including creatinine, blood urea nitrogen (BUN), and kidney injury molecule-1 (Kim-1).
  • Gene expression (Havcr-1), urinary metabolite profiles (NMR, UPLC/MS), and renal pathology were assessed.

Main Results:

  • Ten-day-old rats exhibited the lowest maximum tolerated dose and did not survive prolonged treatment.
  • Eighty-day-old rats showed significant growth reduction, increased serum creatinine, BUN, urinary Kim-1, and renal pathology at the highest dose.
  • Ten- and 40-day-old rats also displayed elevated BUN, creatinine, and renal pathology, while 25-day-old rats showed only mild alterations.
  • Increased Havcr-1 gene expression was observed in 10- and 80-day-old rats after 6 days of treatment.
  • Urinary metabolite analysis revealed changes related to gentamicin efficacy and increased antioxidant activity, particularly in 80-day-old rats.

Conclusions:

  • A multi-age rat model effectively demonstrates age-dependent variations in gentamicin-induced nephrotoxicity.
  • Younger (10-day-old) and older (80-day-old) rats are more susceptible to gentamicin nephrotoxicity than 25-day-old rats.
  • This model serves as a valuable tool for predicting pediatric drug safety in preclinical studies.

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