Nadai M, Hasegawa T, Kato K, Wang L, Nabeshima T, Kato N
Department of Hospital Pharmacy, Nagoya University School of Medicine, Japan.
Antimicrob Agents Chemother. 1993 Sep;37(9):1781-5. doi: 10.1128/AAC.37.9.1781.
The possible alterations in the pharmacokinetics and protein binding behavior of the beta-lactam antibiotic cefazolin (CEZ) were investigated in endotoxemic rats induced by Klebsiella pneumoniae O3 lipopolysaccharide (LPS). LPS (250 micrograms/kg of body weight) was infused for 20 to 30 min 2 h before an intravenous administration of CEZ (20 mg/kg). Significant decreases in systemic clearance and renal clearance of CEZ were observed in LPS-treated rats without any changes in fraction of urinary excretion in unchanged CEZ (> 0.8). The volume of distribution at steady state showed a tendency to increase. The protein binding parameters of CEZ, the binding capacity, and number of binding sites on the albumin molecule were decreased by LPS, whereas the dissociation constant did not change. Significant decreases in systemic and renal clearances for unbound CEZ were observed in LPS-treated rats. The glomerular filtration rate estimated as inulin clearance was also decreased by LPS. The ratio of renal clearance of unbound CEZ to glomerular filtration rate (clearance ratio) dropped to 70% of that in control rats, and the net tubular secretion of CEZ was also dramatically reduced. The present study suggests that LPS has an effect on the pharmacokinetics of CEZ by changes which occur in renal handling and protein binding.
在肺炎克雷伯菌O3脂多糖（LPS）诱导的内毒素血症大鼠中，研究了β-内酰胺抗生素头孢唑林（CEZ）的药代动力学和蛋白结合行为可能发生的改变。在静脉注射CEZ（20mg/kg）前2小时，输注LPS（250μg/kg体重）20至30分钟。在LPS处理的大鼠中观察到CEZ的全身清除率和肾脏清除率显著降低，而未改变的CEZ尿排泄分数（>0.8）没有任何变化。稳态分布容积呈增加趋势。LPS使CEZ的蛋白结合参数、结合能力和白蛋白分子上的结合位点数降低，而解离常数没有变化。在LPS处理的大鼠中观察到未结合CEZ的全身和肾脏清除率显著降低。以菊粉清除率估算的肾小球滤过率也因LPS而降低。未结合CEZ的肾脏清除率与肾小球滤过率之比（清除率比值）降至对照大鼠的70%，CEZ的肾小管净分泌也显著减少。本研究表明，LPS通过肾脏处理和蛋白结合的变化对CEZ的药代动力学产生影响。
