Molecular Aspects of Renal Handling of Aminoglycosides and Strategies for Preventing the Nephrotoxicity

Abstract

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.

Experimental gentamicin-induced nephrotoxicity in the sheep

“…Most of the intravenously administered GM is excreted with urine, whereas a relatively sizable portion is selectively accumulated in the renal cortex, where the concentration of the GM amounts is 50 to 100 times greater than in serum (2). Subsequently, GM remains with a long-half life in the renal proximal tubular cells, leading to renal damage such as structural changes and functional impairments of the plasma membrane, mitochondria, and lysosome (16).…”

“…Therefore, it is administered intravenously, intramuscularly, or locally. It is a low-protein binding drug, filtered through the kidney glomeruli without being metabolised in the body (16). Nephrotoxicity is the main limitation of its therapeutic use (7,14,19).…”

The Effect of Grape Seed Proanthocyanidin Extract in Preventing Amikacin-Induced Nephropathy

“…1 Amikacin (AK) and gentamicin are the two most frequently used AG group antibiotics. 2 Despite several advantages of AGs, including high antibacterial efficacy, rapid onset of action, and low cost, they are associated with significant dose-dependent nephrotoxic effects.…”

Identification of genes involved in gentamicin-induced nephrotoxicity in rats – A toxicogenomic investigation

“…Its tissue specific toxicity is considered to be caused by a selective accumulation of this drug in the tubular epithelial cells in renal cortex, where its concentration is several times higher than in the plasma (Nagai et al, 2004;Goodman et al, 2001;Mingeot-Leclerq and Tulkens, 1999). On the cellular level an intense binding of the drug to the brush border of the proximal tubule could be demonstrated (Moestrup et al, 1995).…”