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Updated: Jun 23, 2026
The Mouse Isolated Perfused Kidney Technique
Published on: November 17, 2016
Renal disposition of colistin in the isolated perfused rat kidney
Zheng Ma1, Jiping Wang, Roger L Nation
1Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
Abstract:
Nephrotoxicity is an important limitation to the clinical use of colistin against Pseudomonas aeruginosa and other gram-negative pathogens. Previous work reported net tubular reabsorption of colistin by the kidney in vivo, but there is no knowledge of its disposition within the kidney. This study investigated the renal disposition and potential transport mechanisms of colistin in the isolated perfused rat kidney (IPK) model by perfusing with colistin sulfate alone (2 microg/ml) or in the presence of potential inhibitors (tetraethylammonium [TEA], glycine-glycine [Gly-Gly], or hydrochloric acid [HCl]) at three different concentrations. When perfused alone, the renal clearances (CL(R)) for colistin A and B (the major components of colistin) in control kidneys were constant and low (mean values < 0.05 ml/min throughout the perfusion). The mean clearance ratios [CR, defined as CL(R)/(f(u) x GFR), where f(u) is the fraction of drug unbound in perfusate and GFR is the glomerular filtration rate] were significantly less than 1. It was concluded that there is net tubular reabsorption of colistin, and this exceeded the reabsorption of water. Less than 10% eliminated from perfusate was recovered in urine, suggesting considerable renal accumulation of colistin. The CR values for colistin were significantly increased when perfused with TEA (500 microM), Gly-Gly (833 microM), and HCl (2,500, 5,000, and 10,000 microM). It is proposed that renal reabsorption of colistin may involve organic cation transporters (inhibited by TEA) and peptide transporters (inhibited by Gly-Gly) and that the process is sensitive to the pH of urine.
Insights
Colistin reabsorption in the kidney involves organic cation and peptide transporters, and is influenced by urine pH. This finding is crucial for understanding colistin nephrotoxicity and optimizing its clinical use.
Area of Science:
- Pharmacology
- Nephrology
- Drug Metabolism
Background:
- Colistin nephrotoxicity limits its clinical application against Gram-negative infections.
- Previous studies indicated net tubular reabsorption of colistin, but its renal disposition remained unknown.
Purpose of the Study:
- To investigate the renal disposition of colistin in an isolated perfused rat kidney (IPK) model.
- To identify potential renal transport mechanisms involved in colistin reabsorption.
Main Methods:
- Perfusion of isolated rat kidneys with colistin sulfate.
- Assessment of colistin clearance and recovery in the presence of potential inhibitors (TEA, Gly-Gly, HCl) and varying pH.
Main Results:
- Colistin exhibited low renal clearance (CL(R)) and clearance ratios (CR) significantly less than 1, indicating net tubular reabsorption exceeding water reabsorption.
- Less than 10% of eliminated colistin was recovered in urine, suggesting significant renal accumulation.
- CR values increased significantly with TEA, Gly-Gly, and HCl, suggesting involvement of specific transporters and pH sensitivity.
Conclusions:
- Net tubular reabsorption of colistin occurs in the kidney, exceeding water reabsorption.
- Renal reabsorption of colistin likely involves organic cation transporters and peptide transporters.
- Colistin renal disposition is sensitive to urine pH, providing insights into nephrotoxicity mechanisms.
