Kacew S, Hewitt W R, Hook J B
Department of Pharmacology, Faculty of Health Sciences, University of Ottawa, Ontario, Canada.
Toxicol Appl Pharmacol. 1989 Jun 1;99(1):61-71. doi: 10.1016/0041-008x(89)90111-7.
Daily subcutaneous administration of 20 or 100 mg/kg gentamicin for 4 days significantly decreased pyridoxal-5'-phosphate and lysosomal specific phosphatidylinositol-phospholipase C (PI-PLC) in newborn rat kidney. The fall in PI-PLC was associated with an elevation in renal phosphatidylinositol, phosphatidylserine, and phosphatidylcholine. The 100 mg/kg gentamicin dose also produced a rise in renal sphingomyelin, phosphatidylethanolamine, phosphatidylglycerol, and total phospholipid (TPL) accompanied by inhibition in the activities of Na+,K+-ATPase and alkaline phosphatase. In contrast, daily intraperitoneal injection of 100 mg/kg vancomycin for 4 days failed to markedly alter renal metabolic parameters. However, the 500 mg/kg vancomycin dose increased kidney weight, TPL, and all individual phospholipid class concentrations accompanied by inhibition of lysosomal specific PI-PLC activity and reduced pyridoxal-5'-phosphate levels. Simultaneous administration of 20 mg/kg gentamicin with either vancomycin dose resulted in renal alterations similar to those produced by gentamicin alone. Concurrent treatment with 100 mg/kg aminoglycoside and either vancomycin dose produced changes in kidney which were similar to those produced by gentamicin alone, except for a synergistic rise in PI as well as a greater fall in alkaline phosphatase and pyridoxal-5'-phosphate. Surprisingly, the concentration of gentamicin and vancomycin was less in newborn kidneys of rats receiving a simultaneous high dose of vancomycin and aminoglycoside treatment compared to levels found in animals given either antibiotic separately. The lack of potentiation of nephrotoxicity in newborns administered a combination of vancomycin and gentamicin may be due to decreased accumulation of either antibiotic in kidney.
每天皮下注射20或100毫克/千克庆大霉素，持续4天，可显著降低新生大鼠肾脏中磷酸吡哆醛-5'-磷酸和溶酶体特异性磷脂酰肌醇-磷脂酶C（PI-PLC）的水平。PI-PLC的下降与肾脏中磷脂酰肌醇、磷脂酰丝氨酸和磷脂酰胆碱的升高有关。100毫克/千克庆大霉素剂量还导致肾脏中鞘磷脂、磷脂酰乙醇胺、磷脂酰甘油和总磷脂（TPL）升高，同时伴有Na +，K + -ATP酶和碱性磷酸酶活性的抑制。相比之下，每天腹腔注射100毫克/千克万古霉素，持续4天，未能显著改变肾脏代谢参数。然而，500毫克/千克万古霉素剂量增加了肾脏重量、TPL以及所有单个磷脂类别的浓度，同时抑制了溶酶体特异性PI-PLC活性并降低了磷酸吡哆醛-5'-磷酸水平。同时给予20毫克/千克庆大霉素与任何一种万古霉素剂量，都会导致与单独使用庆大霉素产生的肾脏改变相似的结果。同时使用100毫克/千克氨基糖苷类药物和任何一种万古霉素剂量，会使肾脏产生与单独使用庆大霉素相似的变化，但PI会协同升高，碱性磷酸酶和磷酸吡哆醛-5'-磷酸的下降幅度更大。令人惊讶的是，与单独给予任何一种抗生素的动物相比，接受高剂量万古霉素和氨基糖苷类药物联合治疗的新生大鼠肾脏中庆大霉素和万古霉素的浓度更低。万古霉素和庆大霉素联合给药的新生儿中肾毒性缺乏增强作用，可能是由于两种抗生素在肾脏中的蓄积减少所致。
