Shiga-Like Toxin II Derived fromEscherichia coliO157:H7 Modifies Renal Handling of Levofloxacin in Rats

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Abstract
The effect of Shiga-like toxin II (SLT-II) (2 μg/animal), which was derived fromEscherichia coliO157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CLR) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio ofp-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-α) and nitrite and nitrate (NOx) in plasma. The TNF-α inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CLRof LVX; in contrast,S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.