Espandiari Parvaneh, Zhang Jun, Rosenzweig Barry A, Vaidya Vishal S, Sun Jinchun, Schnackenberg Laura, Herman Eugene H, Knapton Alan, Bonventre Joseph V, Beger Richard D, Thompson Karol L, Hanig Joseph
Center for Drug Evaluation and Research, Silver Spring, Maryland 20993, USA.
Toxicol Sci. 2007 Oct;99(2):637-48. doi: 10.1093/toxsci/kfm184. Epub 2007 Jul 17.
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.
采用多年龄大鼠模型来确定庆大霉素(GM)暴露后肾损伤中潜在的年龄相关差异。在本研究中,10日龄、25日龄、40日龄和80日龄的Sprague-Dawley大鼠,每天按0、50或100mg/kg体重皮下注射GM,持续6或14天。在首次给药后72小时内收集尿液样本。10日龄大鼠的最大耐受剂量低于其他年龄组(治疗11天无一存活)。给予最高剂量的80日龄大鼠生长速率降低,血清肌酐、血尿素氮(BUN)、尿肾损伤分子-1(Kim-1)升高,且出现肾脏病理改变。给予100mg/kg GM 6天或14天的10日龄和40日龄大鼠血清BUN和Cr水平及肾脏病理也有增加,而25日龄大鼠仅发现轻度肾脏改变。用100mg/kg GM治疗6天后,仅在10日龄和80日龄大鼠中检测到Havcr-1(Kim-1)基因表达显著增加。在尿液样本中,核磁共振和超高效液相色谱/质谱分析检测到与GM疗效相关的变化(如马尿酸盐)以及与抗氧化活性相关的代谢物增加,其中80日龄大鼠增加最为明显。基因组、代谢组和血清化学变化的程度似乎与肾病程度相关。这些发现表明,包含多个发育阶段的实验动物模型可以检测药物诱导的器官毒性中的年龄相关差异,可能是临床前研究中儿科药物安全性的有用预测指标。