Biological and Pharmaceutical Bulletin
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A Rat Model of Early Sepsis: Relationships between Gentamicin Pharmacokinetics and Systemic and Renal Effects of Bacterial Lipopolysaccharide Combined with Interleukin-2
Sarka StudenaJirina MartinkovaDasa SlizovaOtakar KrsMarian SenkerikDrahomira SpringerJaroslav Chládek
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2012 Volume 35 Issue 10 Pages 1703-1710

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Abstract

A rat model of early sepsis induced by lipopolysaccharide (LPS) combined with interleukin-2 (IL-2) was developed. The primary aim was to assess the pharmacokinetics of gentamicin and sepsis-induced pathophysiological changes. Moreover, the effects on the glomerular filtration rate and tubular function were studied in septic and control rats. First, an intravenous (i.v.) bolus of LPSIL-2 (1 mg/kg-Pseudomonas aeruginosa, 15 µg/kg IL-2) or saline (controls, C) was administred. The Wistar rats were treated 30 min after LPSIL-2 with gentamicin as a 3 mg/kg i.v. bolus followed 10 min later by an i.v. 170-min infusion (GE, 0.09 mg/kg·min−1). The monitoring of vital functions, biochemistry and GE concentrations was performed. Creatinine clearance was 2–3 times lower and fractional urea excretion was 3–4 times less in septic rats as compared to controls(p<0.05), although urine flow was comparable. Capillary leakage caused a 55% elevation in the volume of distribution (Vc) in the LPSIL+GE group vs. C+GE (p<0.05). The renal CLge was less (2.2±0.59 vs. 3.8±0.53 mL/min·kg−1, p<0.05), while the total CLge was comparable (5.9±1.5 vs. 6.7±1.1 mL/min·kg−1; p=0.30). In the LPSIL+GE group relative to C+GE, the half-life (t1/2) was 79% higher (p<0.05) and GE concentrations detected at the end of the study in the plasma and kidney were elevated 2.5-fold (p=0.09) and 2.2-fold (p<0.05), respectively. The model reproduced several consequences of early sepsis like in patients such as capillary leak, a decreased glomerular filtration rate (GFR) and the changes in pharmacokinetics of GE (increased values of Vc and t1/2 and a drop in renal CLge proportional to that of CLcr). Nonrenal routes which, for the most part, compensate the reduced renal CLge in septic rats deserve further study.

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© 2012 The Pharmaceutical Society of Japan
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