Sabra R, Branch R A
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Antimicrob Agents Chemother. 1990 Jun;34(6):1020-5. doi: 10.1128/AAC.34.6.1020.
Salt depletion is known to potentiate aminoglycoside nephrotoxicity, while salt replacement attenuates it. Recent studies have shown that ticarcillin protects against tobramycin and gentamicin nephrotoxicity. It has been suggested that this protection is due to an interaction between ticarcillin and the aminoglycoside. However, it can also be explained by the salt load associated with ticarcillin administration. This study was conducted to examine this question. Tobramycin was administered to eight groups of rats at 100 mg/kg per day intraperitoneally for 10 days. Group 1 rats were salt depleted, while group 2 rats were on a normal salt diet. Rats in groups 3 through 8 were also salt depleted but received, in addition, the following interventions intraperitoneally: group 3, ticarcillin, 300 mg/kg per day (0.37 to 0.39 meq of Na supplement per day); group 4, ticarcillin, 300 mg per day (1.56 meq of Na supplement per day); group 5, ticarcillin, 300 mg/kg per day, and NaCl supplement (1.17 to 1.19 meq/day), resulting in a total load of 1.56 meq/day; group 6, piperacillin, 400 mg/day (0.76 meq of Na supplement per day and equimolar to the ticarcillin dose [300 mg/day] in group 4 rats); group 7, piperacillin, 400 mg/day, and NaCl supplement (0.8 meq/day) for a total Na load of 1.56 meq/day; and group 8, 1.56 meq of Na per day as NaCl. Rats in groups 2, 4, 5, 7, and 8, which received a normal salt diet or its equivalent Na supplement, had no significant change in creatinine clearance (CLCR) over the 10-day period. The remaining groups sustained significant reductions in CLCR, as follows: group 1, -53.0% (P < 0.05); group 3, -66.2% (P < 0.05); group 6, -79.8% (P < 0.05). A positive correlation was found between the concentration of tobramycin in the kidneys and the percent change in CLCR at the end of the study. Concentrations of drugs in plasma were highest in group 1 rats, lowest in the rats in groups in which protection was observed, and moderately elevated in the remaining groups of rats. The results of this study suggest the following: (i) that the protective effect of ticarcillin against tobramycin nephrotoxicity is secondary to the obligatory sodium load associated with it, (ii) pharmacokinetic and pharmacodynamic interactions between salt and tobramycin are proposed to explain this effect, (iii) the nephrotoxicity of tobramycin is probably related to the degree of accumulation of the drug in the kidney, and (iv) an in vivo interaction between tobramycin and ticarcillin does not contribute to the protective effect of the penicillin but may influence concentrations in plasma, especially under conditions of severe renal impairment.
已知盐缺失会增强氨基糖苷类药物的肾毒性，而补充盐分则可减轻这种毒性。最近的研究表明，替卡西林可预防妥布霉素和庆大霉素的肾毒性。有人认为这种保护作用是由于替卡西林与氨基糖苷类药物之间的相互作用。然而，这也可以用与替卡西林给药相关的盐负荷来解释。本研究旨在探讨这个问题。将八组大鼠每天以100mg/kg的剂量腹腔注射妥布霉素，持续10天。第1组大鼠盐分缺失，第2组大鼠采用正常盐饮食。第3至8组大鼠也盐分缺失，但另外腹腔内给予以下干预措施：第3组，替卡西林，每天300mg/kg（每天补充0.37至0.39meq的钠）；第4组，替卡西林，每天300mg（每天补充1.56meq的钠）；第5组，替卡西林，每天300mg/kg，并补充氯化钠（每天1.17至1.19meq），钠总负荷为每天1.56meq；第6组，哌拉西林，每天400mg（每天补充0.76meq的钠，与第4组大鼠替卡西林剂量[每天300mg]等摩尔）；第7组，哌拉西林，每天400mg，并补充氯化钠（每天0.8meq），钠总负荷为每天1.56meq；第8组，每天给予1.56meq的氯化钠形式的钠。接受正常盐饮食或等量钠补充的第2、4、5、7和8组大鼠在10天期间肌酐清除率（CLCR）无显著变化。其余组的CLCR持续显著降低，如下：第1组，降低53.0%（P<0.05）；第3组，降低66.2%（P<0.05）；第6组，降低79.8%（P<0.05）。研究结束时，发现肾脏中妥布霉素的浓度与CLCR的百分比变化之间存在正相关。第1组大鼠血浆中的药物浓度最高，观察到有保护作用的组中的大鼠血浆药物浓度最低，其余组大鼠血浆药物浓度中度升高。本研究结果表明：（i）替卡西林对妥布霉素肾毒性的保护作用继发于与之相关的必需钠负荷；（ii）提出盐与妥布霉素之间的药代动力学和药效学相互作用来解释这种作用；（iii）妥布霉素的肾毒性可能与药物在肾脏中的蓄积程度有关；（iv）妥布霉素与替卡西林之间的体内相互作用对青霉素的保护作用无贡献，但可能影响血浆浓度，尤其是在严重肾功能损害的情况下。
