Effect of Endotoxin on P-Glycoprotein-Mediated Biliary and Renal Excretion of Rhodamine-123 in Rats

Author:

Ando Hideyuki1,Nishio Yuki2,Ito Katsuki1,Nakao Akimasa1,Wang Li23,Zhao Ying Lan23,Kitaichi Kiyoyuki2,Takagi Kenzo2,Hasegawa Takaaki2

Affiliation:

1. Department of Second Surgery, Nagoya University School of Medicine,1 and

2. Department of Medical Technology, Nagoya University School of Health Sciences,2 Nagoya, Japan, and

3. National Safety Assessment Center of Traditional Chinese Medicine, Sichuan University of Medical Sciences, Chengdu, China3

Abstract

ABSTRACT The effects of Klebsiella pneumoniae endotoxin on the biliary excretion and renal handling of rhodamine-123 were investigated in rats at different times after intraperitoneal injection (1 mg/kg of body weight). The typical substrates for P glycoprotein, i.e., cyclosporine, colchicine, and erythromycin, inhibited the biliary clearance of rhodamine-123, whereas a substrate for organic cation transporter, cimetidine, did not inhibit clearance, suggesting that rhodamine-123 is transported mainly by P glycoprotein. The biliary, renal, and tubular secretory clearances of rhodamine-123 and the glomerular filtration rate significantly decreased 6 h after injection of endotoxin but returned to control levels by 24 h. These results suggest that endotoxin-induced decreases in P-glycoprotein-mediated biliary excretion and renal handling of rhodamine-123 were probably due to impairment of P-glycoprotein-mediated transport ability. Pretreatment with pentoxifylline (50 mg/kg) significantly inhibited endotoxin-induced increases in tumor necrosis factor alpha (TNF-α) levels in plasma, which ameliorated the endotoxin-induced reduction of the biliary excretion of rhodamine-123. It is likely that endotoxin-induced impairment of the transport of rhodamine-123 is caused, in part, by overproduction of TNF-α. The effect of endotoxin on the expression of P-glycoprotein mRNA in liver and kidneys of rats was investigated by using a reverse transcriptase PCR. The expression of Mdr1a mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control levels after 24 h, whereas the expression of Mdr1b mRNA in liver increased at both times and that in kidney decreased at 24 h. These findings suggest that K. pneumoniae endotoxin dramatically decreases P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 probably by decreasing the expression of Mdr1a, which is likely due to increased plasma TNF-α levels.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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