Effects of intestinal ischemia/reperfusion on P-glycoprotein mediated biliary and renal excretion of rhodamine123 in rat.
To analyze the effects of I/R on P-gp function in liver and kidney, biliary and urinary excretions of rhodamine123 as a substrate of P-gp were examined in rats. The effects of reperfusion time on change and recovery of P-gp function were also examined. The biliary and renal clearance of rhodamine123 significantly decreased at 3 hr after reperfusion, but returned to control levels at 24 hr after reperfusion. These results suggest that intestinal I/R-induced decrease in P-gp-mediated biliary and renal excretion of rhodamine123 is litely due to impairment of P-gp-mediated transport ability. The level of P-gp protein in liver decreased and that of iNOS mRNA increased at 3 hr after reperfusion and both levels returned to control levels at 24 hr after reperfusion. No marked change in the levels of P-gp protein and iNOS mRNA was observed in kidney at 3 hr and 24 hr after reperfusion. Thus, decrease in biliary excretion of rhodamine123 would appear due in part to decrease in expression of P-gp, caused by increase in lipid peroxidation levels through iNOS mRNA.
Tomita
Mikio
M
Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Kishimoto
Hisanao
H
Takizawa
Yusuke
Y
Hayashi
Masahiro
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001659:Biliary Tract / Q000378:metabolism*; D002927:Cimetidine / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D020112:Rhodamine 123 / Q000378:metabolism* / Q000652:urine; D019789:Tetraethylammonium / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020112:Rhodamine 123; D019789:Tetraethylammonium; D002927:Cimetidine; D016572:Cyclosporine; D014700:Verapamil; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat