Calcium is a competitive inhibitor of gentamicin-renal membrane binding interactions and dietary calcium supplementation protects against gentamicin nephrotoxicity.

Humes, H. David; Sastrasinh, Malinee; Weinberg, Joel M.

doi:10.1172/jci111184

Cited by 126 publications

(59 citation statements)

References 31 publications

(43 reference statements)

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“…Sastrasinh et al (47) showed binding of aminoglycosides to acidic phospholipids (25). The Kd for binding of gentamicin to phosphatidylinositol is 170 /iM (48), which is a lower affinity compared to the apparent affinity for gp330 (half maximal inhibition of '251-urokinase-PAI-l binding at 50 /iM gentamicin). However, the receptor affinity of gentamicin and the other polybasic drugs are lower compared to endogenous gp330 ligands, which have Kd 's in the nanomolar range ( 1 1 ).…”

Section: Discussionmentioning

confidence: 99%

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Moestrup¹,

Cui²,

Vorum³

et al. 1995

J. Clin. Invest.

322

233

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Glycoprotein 330 (gp330) is an endocytic receptor expressed in the renal proximal tubules and some other absorptive epithelia, e.g., in the inner ear. The present study shows that the antifibrinolytic polypeptide, aprotinin, and the nephroand ototoxic antibiotics, aminoglycosides, and polymyxin B compete for binding of '"I-urokinase-plasminogen activator inhibitor type-i complexes to purified rabbit gp330. Half maximal inhibition was measured at 4 ,uM for aprotinin, 50 tiM for gentamicin, and 0.5 tiM for polymyxin B. Drug binding to gp330 was validated by equilibrium dialysis of [3H]gentamicin-gp330 incubations and binding/uptake studies in rat proximal tubules and gp330-expressing L2 carcinoma cells. Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae revealed that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human a2-macroglobulin receptor. However, the rapid glomerular filtration of the drugs suggests kidney gp330 to be the quantitatively most important target.In conclusion, a novel role of gp330 as a drug receptor is demonstrated. The new insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for future design of drugs with reduced toxicity. (J. Clin.

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Section: Discussionmentioning

confidence: 99%

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Moestrup¹,

Cui²,

Vorum³

et al. 1995

J. Clin. Invest.

322

233

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“…Polymyxin B, a positively charged cyclic polypeptide antibiotic, perturbs a cytoplasmic membrane by interaction with phosphatidylethanolamine (7) and alters permeability in Escherichia coli (6). The antibacterial activities of these antibiotics are reversed by CaC12 (5,11). These antibiotics are also sporocidal or sporostatic for B. subtilis spores under certain limited conditions and reversed by CaCl2.…”

Section: Discussionmentioning

confidence: 99%

Permeability of Gentamicin and Polymyxin B into the Inside of Bacillus subtilis Spores

Fujita

Yasuda

Tochikubo

1990

Microbiology and Immunology

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The penetration of gentamicin and polymyxin B into the inside of Bacillus subtilis spores was examined by an immunoelectron microscopy method with colloidalThe colloidal gold particles were located predominantly in the coat region of both gentamicin-treated and polymyxin Btreated spores and were hardly observed in the other regions, i.e., the cortex and core regions.When these antibiotic-treated spores were subsequently treated with CaCl2, the number of gold particles bound to the coat region was greatly decreased. These results suggest that these two antibiotics are able to penetrate into the spore coat but not into the cortex or core, that is, the primary permeability barrier to them exists between the coat and the cortex regions.

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“…Also a reduction in the binding with brush-border of the membrane has been tried, altering the pH of the urine using bicarbonate [62] and using competitors to bind on the brush-border such as calcium [63] and lysine [64]. All these studies proved to have little clinical applicability as they diminished the efficacy of the drug or caused high toxicity.…”

Section: Experimental Studiesmentioning

confidence: 99%

<![CDATA[<B>Aminoglycoside nephrotoxicity</B>]]>

Oliveira¹,

Cipullo²,

Burdmann³

2006

Braz. j. cardiovasc. surg.

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Aminoglycoside are frequently used due to its high efficacy against gram-negative bacteria and positive synergism with other antibiotics against gram-positive organisms. They are commonly used for prevention and treatment of infection complications after cardiothoracic surgery. The principal side effect of this class of antibiotics is nephrotoxicity, which may occur in up to 20% of the exposed patients. Although usually reversible, aminoglycosideinduced renal injury prolongs hospitalization time and increase patients cost. Even more important, the occurrence of nephrotoxicity is associated with higher patient mortality. There are some known risk factors for nephrotoxicity development and some measures that may prevent it. This review will cover the most relevant aspects of this important side effect of aminoglycoside therapy. Descriptors 445OLIVEIRA, JFP ET AL -Aminoglycoside nephrotoxicity Braz J Cardiovasc Surg 2006; 21(4): 444-452

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Calcium is a competitive inhibitor of gentamicin-renal membrane binding interactions and dietary calcium supplementation protects against gentamicin nephrotoxicity.

Cited by 126 publications

References 31 publications

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Permeability of Gentamicin and Polymyxin B into the Inside of Bacillus subtilis Spores

<![CDATA[<B>Aminoglycoside nephrotoxicity</B>]]>

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