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Antimicrobial Agents and Chemotherapy, May 2002, p. 1522-1528, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1522-1528.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Shiga-Like Toxin II Derived from Escherichia coli O157:H7 Modifies Renal Handling of Levofloxacin in Rats

Department of Medical Technology, Nagoya University School of Health Sciences,¹ Department of Pathology,³ Department of Bacteriology, Nagoya University School of Medicine,⁴ Faculty of Pharmacy, Meijo University, Nagoya, Japan,⁵ National Safety Assessment Center of Traditional Chinese Medicine, First University Hospital, Sichuan University, Chengdu, China²

Received 9 April 2001/ Returned for modification 26 September 2001/ Accepted 31 January 2002

The effect of Shiga-like toxin II (SLT-II) (2 µg/animal), which was derived from Escherichia coli O157: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 (CL_R) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-) and nitrite and nitrate (NOx) in plasma. The TNF- inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL_R of 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.

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