Slighter R G, Montenaro M J, Fabian R J, Bhandari J C, Donikian M R, Drobeck H P
Fundam Appl Toxicol. 1984 Aug;4(4):558-67. doi: 10.1016/0272-0590(84)90045-9.
The nephrotoxicity of hydroxygentamicin and amikacin was examined in young adult Fischer 344 rats. Serum creatinine (SCr) and urea nitrogen (BUN) levels were not significantly affected following sc injection of 80 or 160 mg/kg/day of hydroxygentamicin for 15 days. However, 250 mg/kg of amikacin produced significant increases in both parameters and in kidney/body weight ratios. The ratios were also significantly increased after 80 or 160 mg/kg of hydroxygentamicin, but kidneys of rats receiving amikacin were considerably heavier than those of rats treated with hydroxygentamicin. The antibacterial potency of 250 mg/kg of amikacin is comparable to that of 100 mg/kg of hydroxygentamicin. Additional studies, directly comparing hydroxygentamicin, a mutational biosynthetic, with gentamicin or netilmicin, all at 40, 80, and 160 mg base/kg, and incorporating renal function parameters as well as SCr, BUN, organ weight, tissue concentration, and kidney histopathology, revealed a characteristic pattern typical of aminoglycoside nephrotoxicity in mature adult male rats. In most parameters, values in rats given hydroxygentamicin or netilmicin were normal and comparable to those in controls, but kidney/body weight ratios were significantly increased at high doses. However, kidneys of rats medicated with gentamicin at comparable doses were considerably heavier than those of hydroxygentamicin-treated rats. Significant nephrotoxicity also was seen in rats given low doses of gentamicin or netilmicin. Eosinophilic granulation and vacuolization of renal proximal tubular epithelium, interstitial inflammation, and tubular dilation were observed microscopically with all three drugs in the following descending order of severity: gentamicin greater than netilmicin greater than hydroxygentamicin. The effects on proximal tubular epithelial cells following treatment with amikacin, netilmicin, or hydroxygentamicin correlated reasonably well with renal drug concentrations, but drug concentrations of gentamicin, which produced the most extensive kidney injury, were lower than those of the other three aminoglycosides. Elevated SCr or BUN were indicative of the presence of nephrosis, but early stages of tubular epithelial degeneration were not predicted by increases in BUN or SCr. Although minimal or mild nephrosis was seldom predicted by polyuria, proteinuria, or changes in osmolality, effects observed in renal function parameters usually correlated well with renal histopathology. However, a decrease in osmolality correlated best with enlarged kidneys and changes in renal morphology.
在成年雄性Fischer 344大鼠中研究了庆大霉素和阿米卡星的肾毒性。皮下注射80或160mg/kg/天的庆大霉素，持续15天，血清肌酐（SCr）和尿素氮（BUN）水平未受到显著影响。然而，250mg/kg的阿米卡星使这两个参数以及肾/体重比均显著增加。80或160mg/kg的庆大霉素也使该比值显著增加，但接受阿米卡星治疗的大鼠肾脏比接受庆大霉素治疗的大鼠肾脏重得多。250mg/kg阿米卡星的抗菌效力与100mg/kg庆大霉素的抗菌效力相当。进一步的研究直接比较了庆大霉素（一种突变生物合成的药物）与庆大霉素或奈替米星，剂量均为40、80和160mg碱基/kg，并纳入了肾功能参数以及SCr、BUN、器官重量、组织浓度和肾脏组织病理学，揭示了成年雄性大鼠中典型的氨基糖苷类肾毒性特征模式。在大多数参数中，给予庆大霉素或奈替米星的大鼠的值正常，与对照组相当，但高剂量时肾/体重比显著增加。然而，给予相当剂量庆大霉素的大鼠肾脏比接受庆大霉素治疗的大鼠肾脏重得多。给予低剂量庆大霉素或奈替米星的大鼠也出现了显著的肾毒性。用这三种药物显微镜观察到肾近端小管上皮细胞嗜酸性颗粒形成和空泡化、间质炎症和小管扩张，严重程度依次为：庆大霉素＞奈替米星＞庆大霉素。用阿米卡星、奈替米星或庆大霉素治疗后对近端小管上皮细胞的影响与肾脏药物浓度有较好的相关性，但造成最广泛肾损伤的庆大霉素的药物浓度低于其他三种氨基糖苷类药物。SCr或BUN升高表明存在肾病，但BUN或SCr升高并不能预测小管上皮细胞变性的早期阶段。虽然多尿、蛋白尿或渗透压变化很少能预测轻微或轻度肾病，但肾功能参数中观察到的影响通常与肾脏组织病理学有很好的相关性。然而，渗透压降低与肾脏肿大和肾脏形态变化的相关性最好。
