Shiga-like toxin II derived from Escherichia coli O157:H7 modifies renal handling of levofloxacin in rats.
The effect of Shiga-like toxin II (SLT-II) (2 microg/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-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha 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.
Zhao
Ying Lan
YL
Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
Cen
Xiao Bo
XB
Ito
Masafumi
M
Yokoyama
Keiko
K
Takagi
Kenji
K
Kitaichi
Kiyoyuki
K
Nadai
Masayuki
M
Ohta
Michio
M
Takagi
Kenzo
K
Hasegawa
Takaaki
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000652:urine; D002352:Carrier Proteins / Q000378:metabolism; D019453:Escherichia coli O157 / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D064704:Levofloxacin; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D015242:Ofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D022641:Shiga Toxin 2 / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000890:Anti-Infective Agents; D002352:Carrier Proteins; D022641:Shiga Toxin 2; D064704:Levofloxacin; D015242:Ofloxacin