Correlation between renal membrane binding and nephrotoxicity of aminoglycosides

Abstract

The kinetics of aminoglycoside binding to renal brush border and basolateral membrane vesicles from rat renal cortex were studied by using [3H]amikacin.[3H]amikacin binding to renal membranes was found to be a rapid, saturable process with a fourfold greater affinity for basolateral membranes than for brush border membranes (Kd basolateral = 607 ,uM; Kd brush border = 2,535 ,uM). Renal membranes prepared from immature rats (2 to 3 weeks old) exhibited a significantly lower affinity compared with membranes from adults (Kd basolateral = 2,262 ,uM; Kd brush border = 6,216 ,uM). Additionally, the inhibitory behavior of several aminoglycosides versus [3H]amikacin binding to brush border membranes revealed the following rank order of potency: neomycin > tobramycin gentamicin netilmicin > amikacin neamine > streptomycin. The relative insensitivity of immature rats to aminoglycoside-induced nephrotoxicity in vivo and the comparative nephrotoxicity of the various aminoglycosides suggest that renal membrane-binding affinity is closely correlated to the nephrotoxic potential of these antibiotics.Aminoglycoside antibiotics are nephrotoxic in humans and experimental animals, in which they induce necrosis of the proximal tubule (4,13,26). The nephrotoxicity of these drugs is associated with selective accumulation of aminoglycosides in the kidney, with cortical levels reaching as high as 20 times the circulating levels in serum (10, 40). Aminoglycosides are known to accumulate in renal tissue via tubular reabsorption as well as by extraction from the circulation at the basolateral surface of the kidney, although brush border uptake is thought to contribute more on a quantitative basis (6,7,17,34). However, it remains to be established whether the nephrotoxicity is a consequence of accumulated drug or relates to an interaction at the initial point of contact between the renal cell and the aminoglycoside, the plasma membrane. Williams et al. (43) recently reported the inhibition of aminoglycoside nephrotoxicity by polyamino acids associated with decreased renal brush border and basolateral membrane binding without inhibition of total cortical accumulation. Effects of aminoglycosides on plasma membrane structure and function have been reported (11,20,29,36,44).To examine the possible correlation between renal membrane binding and the nephrotoxicity of aminoglycosides, it is appropriate to compare the relative affinity of the various aminoglycosides for the membrane-binding site. Renal membrane-binding kinetics have been described for gentamicin (18,28,42)

Megalin Deficiency Offers Protection from Renal Aminoglycoside Accumulation

“…Thus, aminoglycoside derivatives with reduced tendency to accumulate in the renal cortex also proved less nephrotoxic (35). Given its central role in renal aminoglycoside uptake, megalin activity can be assumed to be a critical factor contributing to aminoglycoside-induced nephrotoxicity.…”

Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects. (8): Protective effect of pyridoxal-5'-phosphate against tobramycin nephrotoxicity.

“…This result was in agree ment with the observation reported by Kacew (10), using gentamicin and PALP. It has been shown that spermine, a polyamine, reduced the gentamicin uptake in the rat kidney cortex (11) and that the binding of gentamicin to rat BBMs was inhibited by spermine (12). These observations suggested that reduction of intrarenal gentamicin level was associated with the inhibition of gentamicin binding to BBMs.…”

Neamine is preferential as an anti-prostate cancer reagent by inhibiting cell proliferation and angiogenesis, with lower toxicity than cis-platinum

“…Previous studies indicated that the expression of angiogenin increased along with the progression of prostate cancer (15), and that the plasma angiogenin level was elevated in prostate cancer patients, particularly in hormonal refractory prostate cancer patients (13). Neomycin and neamine were found to inhibit the nuclear translocation of angiogenin (26), but neamine had much less toxicity than neomycin (27,28). PC-3 cells are a type of hormone-independent prostate cancer cell, and in the present study, it was demonstrated that neamine blocked the translocation of angiogenin in the PC-3 cells, with an effect that was comparable to DDP in PC-3 xenografts, but with much lower toxicity.…”