Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity.
Aminoglycosides such as gentamicin and amikacin are the most commonly used antibiotics worldwide in the treatment of Gram-negative bacterial infections. However, serious complications like nephrotoxicity and ototoxicity are dose-limiting factors in the use of aminoglycosides. A relatively large amount of the intravenously administered dose is accumulated in the kidney (about 10% of dose), whereas little distribution of aminoglycosides to other tissues is observed. Aminoglycosides are taken up in the epithelial cells of the renal proximal tubules and stay there for a long time, resulting in nephrotoxicity. Acidic phospholipids are considered as a binding site for aminoglycosides in the brush-border membrane of the proximal tubular cells. More recently, it has been reported that megalin, a giant endocytic receptor abundantly expressed at the apical membrane of renal proximal tubules, plays an important role in binding and endocytosis of aminoglycosides in the proximal tubular cells. The elucidation of the aminoglycoside-binding receptor would help design a strategy to prevent against aminoglycoside-induced nephrotoxicity. In this review, we summarize recent advances in the understandings of the molecular mechanisms responsible for renal accumulation of aminoglycosides, especially megalin-mediated endocytosis. In addition, approaches toward prevention of aminoglycoside-induced nephrotoxicity are discussed, based on the molecular mechanisms of the renal accumulation of aminoglycosides.
Nagai
Junya
J
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Japan.
Takano
Mikihisa
M
D000617:Aminoglycosides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents