Published ETD Collection
Permanent URI for this collectionhttps://hdl.handle.net/10657/2
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Browsing Published ETD Collection by Author "Abdelraouf, Kamilia"
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Item Characterization of Pharmacokinetics and Nephrotoxicity of Polymyxin B(2012-12) Abdelraouf, Kamilia; Tam, Vincent H.; Hu, Ming; Chow, Diana Shu-Lian; Trivedi, Meghna V.; Truong, Luan D.Objective: Increasing prevalence of multidrug resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the pharmacological properties of polymyxin B are still poorly understood. The objective of this study was to characterize the pharmacokinetics, renal disposition and nephrotoxicity of systemic polymyxin B. Methods: Pharmacokinetic parameters of the different polymyxin B components following intravenous administration in rats were derived and compared. Renal recovery and kidney concentration of polymyxin B were evaluated. In addition, the pharmacokinetics of polymyxin B was estimated in renal insufficiency and compared to those observed in normal renal function. Finally, the nephrotoxicity potential was evaluated in vitro and in vivo; the impact of dosing frequency on the onset of nephrotoxicity was examined. Results: The pharmacokinetic parameters of the major components did not appear to be significantly different. Prolonged residence of polymyxin B in kidneys was observed. Less than 1% of the dose was recovered unchanged in urine. The pharmacokinetics of polymyxin B was not significantly altered by renal insufficiency. Polymyxin B was toxic to renal cells in vitro. In vivo, polymyxin Binduced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. The onset of nephrotoxicity was dose-dependent; more frequent dosing appeared to be associated with earlier onset of nephrotoxicity. Conclusion: Polymyxin B components have similar pharmacokinetics. Mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. Polymyxin B induced nephrotoxicity, which could be attributed to drug accumulation in kidneys and appeared to be dependent on the dose as well as the dosing frequency.