Inouye S, Niizato T, Komiya I, Yuda Y, Yamada Y
J Pharmacobiodyn. 1982 Dec;5(12):941-50. doi: 10.1248/bpb1978.5.941.
We studied the mechanism on protective effect of fosfomycin against experimental nephrotoxicity induced by dibekacin. In order to simplify an experimental model, the dehydrated Wistar rats were used, because a single injection of dibekacin at 30 mg/kg induced acute renal failure in the dehydrated rats, characterized by alteration of urinalytic parameters and BUN values, and retarded elimination of dibekacin from blood. When the rats were administered simultaneously with fosfomycin at 120 mg/kg, the rate of elimination was restored almost to normal, accompanied with improvement of the nephrotoxic parameters. However, markedly accelerated elimination over normal one was not observed, indicating that the improved elimination was not the reason of protection but a result of normal kidney function. On the other hand, fosfomycin protected the proximal tubular lysosomes from the injury of aminoglycoside, as evidenced a) in vivo by suppression of myeloid body formation and protection of lysosomal membrane integrity of the rats treated with dibekacin, and b) in vitro by dose-dependent protection of the lysosomal membrane integrity of the kidney cells. A study of structure-protective activity relation revealed that phosphonate anion possessing an epoxy function was important for protection, and that the mechanism of protection differed from the antibacterial mechanism.
我们研究了磷霉素对双去氧卡那霉素诱导的实验性肾毒性的保护作用机制。为了简化实验模型，使用了脱水的Wistar大鼠，因为以30mg/kg单次注射双去氧卡那霉素可在脱水大鼠中诱导急性肾衰竭，其特征为尿液分析参数和血尿素氮值的改变，以及双去氧卡那霉素从血液中的消除延迟。当大鼠同时接受120mg/kg的磷霉素给药时，消除速率几乎恢复正常，同时肾毒性参数得到改善。然而，未观察到消除速率明显加速超过正常水平，这表明消除改善不是保护的原因，而是肾功能正常的结果。另一方面，磷霉素保护近端肾小管溶酶体免受氨基糖苷类的损伤，这在体内表现为抑制髓样体形成并保护用双去氧卡那霉素处理的大鼠的溶酶体膜完整性，在体外表现为对肾细胞溶酶体膜完整性的剂量依赖性保护。结构-保护活性关系研究表明，具有环氧功能的膦酸根阴离子对保护很重要，并且保护机制不同于抗菌机制。
