Uptake of Polymyxin B into Renal Cells

ABSTRACT Polymyxin B is increasingly used as a treatment of last resort against multidrug-resistant Gram-negative infections. Using a mammalian kidney cell line, we demonstrated that polymyxin B uptake into proximal tubular epithelial cells was saturable and occurred primarily through the apical membrane, suggesting the involvement of transporters in the renal uptake of polymyxin B. Megalin might play a role in the uptake and accumulation of polymyxin B into renal cells.

[1]  V. Tam,et al.  A validated ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of polymyxin B in mouse serum and epithelial lining fluid: application to pharmacokinetic studies. , 2013, The Journal of antimicrobial chemotherapy.

[2]  Vagelos Pr Innovation and industry-academia interactions: where conflicts arise and measures to avoid them. , 2007 .

[3]  D. Pompliano,et al.  Drugs for bad bugs: confronting the challenges of antibacterial discovery , 2007, Nature Reviews Drug Discovery.

[4]  A. Bonvin,et al.  Gentamicin Binds to the Megalin Receptor as a Competitive Inhibitor Using the Common Ligand Binding Motif of Complement Type Repeats , 2012, The Journal of Biological Chemistry.

[5]  G. Turett,et al.  Polymyxin B Nephrotoxicity and Efficacy against Nosocomial Infections Caused by Multiresistant Gram-Negative Bacteria , 2003, Antimicrobial Agents and Chemotherapy.

[6]  H. Yamaguchi,et al.  Megalin Contributes to Kidney Accumulation and Nephrotoxicity of Colistin , 2013, Antimicrobial Agents and Chemotherapy.

[7]  D. Kerjaschki,et al.  The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[8]  L. Rice Emerging issues in the management of infections caused by multidrug-resistant gram-negative bacteria. , 2007, Cleveland Clinic journal of medicine.

[9]  A. Gales,et al.  Intravenous polymyxin B for the treatment of nosocomial pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. , 2007, International journal of antimicrobial agents.

[10]  J. Handler,et al.  Use of cultured epithelia to study transport and its regulation. , 1983, The Journal of experimental biology.

[11]  F. Luft,et al.  Megalin Deficiency Offers Protection from Renal Aminoglycoside Accumulation* , 2002, The Journal of Biological Chemistry.

[12]  K. Kishi,et al.  In vitro and in vivo potency of polymyxin B against IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa. , 2008, International journal of antimicrobial agents.

[13]  Ming Hu,et al.  Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design , 2012, Antimicrobial Agents and Chemotherapy.

[14]  V. Tam,et al.  Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model , 2012, Antimicrobial Agents and Chemotherapy.

[15]  S. Moestrup,et al.  Characterization of a kidney proximal tubule cell line, LLC-PK1, expressing endocytotic active megalin. , 1998, Journal of the American Society of Nephrology : JASN.

[16]  P. Verroust,et al.  Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli. I. Renal distribution. , 1986, The American journal of pathology.

[17]  Yehuda Carmeli,et al.  Clinical and Economic Impact of Common Multidrug-Resistant Gram-Negative Bacilli , 2007, Antimicrobial Agents and Chemotherapy.

[18]  V. Tam,et al.  Variability of polymyxin B major components in commercial formulations. , 2010, International journal of antimicrobial agents.

[19]  Jian Li,et al.  Polymyxin B for the treatment of multidrug-resistant pathogens: a critical review. , 2007, The Journal of antimicrobial chemotherapy.

[20]  D. Calfee,et al.  Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy. , 2012, The Journal of infection.

[21]  S. Hammer,et al.  Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. , 2004, The Journal of antimicrobial chemotherapy.

[22]  W. Pfaller,et al.  Biochemical characterization of renal epithelial cell cultures (LLC-PK1 and MDCK). , 1985, American Journal of Physiology.

[23]  P. Verroust,et al.  Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli. II. Extrarenal distribution. , 1986, The American journal of pathology.

[24]  S. Moestrup,et al.  Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. , 1995, The Journal of clinical investigation.

[25]  B. Gilliam,et al.  Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.