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Effects of polymyxin antibiotics on iodohippurate accumulation in rabbit renal cortical slices
Abstract:
The in vitro effects of polymyxin antibiotics on 0-125I-hippurate (OIH) accumulation in rabbit renal cortical slices were studied using incubation media with pH ranging from 6.9 to 7.9 and containing polymyxin B sulfate, colistin sulfate, sodium colistimethate and antibacterially inactive N-succinyl colistin in concentrations ranging from 1 to 2,000 microgram base/ml. Polymyxin B, colistin and colistimethate depressed OIH accumulation significantly in concentrations greater than or equal to 300 microgram/ml. The effects on accumulation were clearly pH-dependent and most pronounced at alkaline pH. N-Succinyl colistin had only a marginal influence on accumulation, even in high concentrations. Colistimethate produced a significantly smaller decrease in accumulation at all pH values than both polymyxin B and colistin. The results suggest that the presence of free amino groups is necessary to obtain a decrease in accumulation and correlate with the known in vivo nephrotoxicity of these antibiotics.
Insights
Polymyxin antibiotics, like polymyxin B and colistin, significantly reduce kidney cell uptake of OIH at high doses. This effect is pH-dependent, highlighting a link to antibiotic nephrotoxicity.
Area of Science:
- Pharmacology
- Nephrology
- Toxicology
Background:
- Polymyxin antibiotics are crucial for treating multidrug-resistant Gram-negative infections.
- Their use is limited by significant nephrotoxicity.
- The precise mechanisms underlying polymyxin-induced kidney damage remain under investigation.
Purpose of the Study:
- To investigate the in vitro effects of various polymyxin antibiotics on organic anion transport in rabbit renal cortical slices.
- To determine the influence of pH and antibiotic structure on the inhibition of 0-125I-hippurate (OIH) accumulation.
- To correlate in vitro findings with known in vivo nephrotoxicity.
Main Methods:
- Incubation of rabbit renal cortical slices with varying concentrations (1-2,000 µg/ml) of polymyxin B, colistin, sodium colistimethate, and N-succinyl colistin.
- Measurement of 0-125I-hippurate (OIH) accumulation at different media pH values (6.9-7.9).
- Statistical analysis to assess the significance of observed effects.
Main Results:
- Polymyxin B, colistin, and colistimethate significantly inhibited OIH accumulation at concentrations ≥300 µg/ml.
- Inhibitory effects were pH-dependent, being most pronounced at alkaline pH.
- N-Succinyl colistin showed minimal impact; colistimethate was less inhibitory than polymyxin B and colistin.
Conclusions:
- The presence of free amino groups in polymyxins appears necessary for inhibiting OIH accumulation.
- The pH-dependent inhibition suggests a role for charge interactions in the nephrotoxic mechanism.
- These in vitro findings support the correlation between polymyxin structure, transport inhibition, and in vivo nephrotoxicity.