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Role of megalin in renal handling of aminoglycosides

J Nagai1, H Tanaka, N Nakanishi

  • 1Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima University, Hiroshima 734-8551, Japan.

American Journal of Physiology. Renal Physiology
|July 18, 2001
PubMed

Insights

Megalin facilitates aminoglycoside accumulation in the kidney. This protein mediates drug uptake, with its levels directly correlating to amikacin concentration in renal tissues.

Area of Science:

  • Pharmacology
  • Nephrology
  • Biochemistry

Background:

  • Aminoglycosides are crucial antibiotics, but their renal toxicity necessitates understanding their tissue distribution.
  • Megalin, a scavenger receptor, is expressed in the renal brush-border membrane and known to bind various ligands.

Purpose of the Study:

  • To investigate the role of megalin in the renal tissue distribution and accumulation of aminoglycoside antibiotics in vivo.
  • To explore the potential competitive interaction between aminoglycosides, calcium, and other megalin ligands in the kidney.

Main Methods:

  • Comparative study in normal and maleate-treated rats (megalin-deficient).
  • Intravenous administration of amikacin and gentamicin.
  • Measurement of drug and megalin ligand levels in various tissues.
  • Ligand blotting assays to assess binding interactions.

Main Results:

  • Amikacin predominantly accumulated in the renal cortex and medulla of normal rats, correlating with megalin levels.
  • Gentamicin administration increased urinary excretion of megalin ligands, indicating competitive binding.
  • Aminoglycosides inhibited the binding of calcium to megalin in vitro.
  • Maleate treatment reduced both megalin and amikacin in the renal cortex, with recovery linked to megalin levels.

Conclusions:

  • Megalin plays a significant role in the renal cortical accumulation of aminoglycosides.
  • Competition between aminoglycosides, calcium, and other ligands for megalin binding may influence drug distribution and kidney handling.

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