![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
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.
This article has been cited by other articles:
|
|
 |
|
  J. Mishra, Q. Zhang, J. L. Rosson, J. Moran, J. M. Dopp, and B. L. Neudeck Lipopolysaccharide Increases Cell Surface P-glycoprotein That Exhibits Diminished Activity in Intestinal Epithelial Cells Drug Metab. Dispos., October 1, 2008; 36(10): 2145 - 2149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Morgan, K. B. Goralski, M. Piquette-Miller, K. W. Renton, G. R. Robertson, M. R. Chaluvadi, K. A. Charles, S. J. Clarke, M. Kacevska, C. Liddle, et al. Regulation of Drug-Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer Drug Metab. Dispos., February 1, 2008; 36(2): 205 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Maeng, M.-H. Kim, H.-E. Jin, S. M. Shin, T. Tsuruo, S. G. Kim, D.-D. Kim, C.-K. Shim, and S.-J. Chung Functional Induction of P-glycoprotein in the Blood-Brain Barrier of Streptozotocin-Induced Diabetic Rats: Evidence for the Involvement of Nuclear Factor-{kappa}B, a Nitrosative Stress-Sensitive Transcription Factor, in the Regulation Drug Metab. Dispos., November 1, 2007; 35(11): 1996 - 2005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Petrovic, S. Teng, and M. Piquette-Miller REGULATION OF DRUG TRANSPORTERS: DURING INFECTION AND INFLAMMATION Mol. Interv., April 1, 2007; 7(2): 99 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zhang, T. M. C. Tan, and L.-Y. Lim Impact of Curcumin-Induced Changes in P-Glycoprotein and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats Drug Metab. Dispos., January 1, 2007; 35(1): 110 - 115. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
