Characterization of Pharmacokinetics and Nephrotoxicity of Polymyxin B
| dc.contributor.advisor | Tam, Vincent H. | |
| dc.contributor.committeeMember | Hu, Ming | |
| dc.contributor.committeeMember | Chow, Diana Shu-Lian | |
| dc.contributor.committeeMember | Trivedi, Meghna V. | |
| dc.contributor.committeeMember | Truong, Luan D. | |
| dc.creator | Abdelraouf, Kamilia | |
| dc.date.accessioned | 2018-03-14T17:28:19Z | |
| dc.date.available | 2018-03-14T17:28:19Z | |
| dc.date.created | December 2012 | |
| dc.date.issued | 2012-12 | |
| dc.date.submitted | December 2012 | |
| dc.date.updated | 2018-03-14T17:28:19Z | |
| dc.description.abstract | 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. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/2971 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Renal insufficiency | |
| dc.subject | Renal uptake | |
| dc.subject | Renal excretion | |
| dc.subject | Kidney health | |
| dc.title | Characterization of Pharmacokinetics and Nephrotoxicity of Polymyxin B | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| thesis.degree.discipline | Pharmaceutics | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Pharmaceutics |