Nadai M, Hasegawa T, Kato K, Wang L, Nabeshima T, Kato N
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
J Pharm Pharmacol. 1993 Nov;45(11):971-4. doi: 10.1111/j.2042-7158.1993.tb05638.x.
The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg-1) and inulin (100 mg kg-1) were administered intravenously 2 h after administration of 50, 250 or 500 micrograms kg-1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 micrograms kg-1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.
在大鼠中研究了肺炎克雷伯菌O3脂多糖对氨基糖苷类药物妥布霉素肾脏处理及分布特征的影响。在给予50、250或500微克/千克脂多糖2小时后，静脉注射妥布霉素（2毫克/千克）和菊粉（100毫克/千克）。脂多糖以剂量依赖性方式延迟了妥布霉素从血浆中的消失。观察到妥布霉素的全身清除率呈剂量依赖性降低，尽管在任何组中未变化药物的消除速率常数和尿回收率分数均无显著差异。脂多糖显著降低了妥布霉素的中央室分布容积，但不影响稳态分布容积。观察到转运至外周室的速率常数与从外周室转运至中央室的速率常数之比呈剂量相关增加。用250微克/千克脂多糖预处理显著降低了肾小球滤过率，清除率降低了20%，表明脂多糖增加了妥布霉素的肾小管重吸收。我们的研究结果表明，肺炎克雷伯菌O3脂多糖改变了肾小球滤过率和肾小管重吸收，而终末半衰期无变化，并且从快速分布室到外周室的药物分布特征发生改变，而细胞外液体积未扩大。
