Impact of endotoxin-induced changes in P-glycoprotein expression on disposition of doxorubicin in mice.
P-glycoprotein (PGP) encoded by the Mdr1 gene mediates the excretion of drugs in organs such as the liver and kidney. Inflammation has been shown to suppress the expression and activity of PGP in rodent liver, thus potentially altering the pharmacokinetics of drugs that are substrates of PGP. Here we examined the effect of endotoxin (lipopolysaccharide; LPS)-induced inflammation on the disposition of the PGP substrate doxorubicin (DOX) in the mouse. Male CD-1 mice received 5 mg/kg LPS intraperitoneally. DOX (5 mg/kg) was administered intravenously 24 h after LPS treatment. The time course of DOX levels in plasma, urine, bile, and tissues was analyzed by high performance liquid chromatography. PGP protein and mRNA expression in liver and kidney was measured using Western blots and reverse transcriptase polymerase chain reaction. As compared to controls, LPS-treated mice exhibited a significant decrease (50%) in biliary clearance and 3-fold increased renal clearance of DOX. These changes were associated with strongly reduced PGP protein levels (30% controls, p < 0.05) in the liver and increased PGP levels in the kidney (140% controls, p < 0.05). Hepatic mRNA levels of all Mdr isoforms were reduced in LPS-treated mice, whereas renal Mdr1b levels were increased. In LPS-treated mice, we also measured an increased area under the plasma concentration-time curve and reduced systemic clearance of DOX, as well as a 2- to 5-fold increase in the urinary excretion of the doxorubicin and doxorubicinol aglycones. Our data suggest that endotoxin-induced inflammation in mice causes differential regulation of PGP in liver and kidney, thereby altering the clearance profile of DOX.
Hartmann
Georgy
G
Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario M5S 2S2, Canada.
Vassileva
Vessela
V
Piquette-Miller
Micheline
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D004317:Doxorubicin / Q000097:blood / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004731:Endotoxins; D008070:Lipopolysaccharides; D004317:Doxorubicin