title: The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.
abstract: 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.
authors.affiliation: Center for Drug Evaluation and Research, Silver Spring, Maryland 20993, USA. parvaneh.espandiari@fda.hhs.gov
authors.forename: Parvaneh
authors.initials: P
authors.lastname: Espandiari
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Barry A
authors.initials: BA
authors.lastname: Rosenzweig
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
authors.forename: Jinchun
authors.initials: J
authors.lastname: Sun
authors.forename: Laura
authors.initials: L
authors.lastname: Schnackenberg
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.forename: Karol L
authors.initials: KL
authors.lastname: Thompson
authors.forename: Joseph
authors.initials: J
authors.lastname: Hanig
mesh_terms: D000367:Age Factors; D000818:Animals; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects; D013058:Mass Spectrometry; D023421:Models, Animal; D053495:Osteopontin / Q000235:genetics; D010372:Pediatrics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013154:Spleen / Q000187:drug effects; D000074050:TWEAK Receptor
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C506897:Spp1 protein, rat; D000074050:TWEAK Receptor; D053495:Osteopontin