Revisiting Polymyxin B: Pharmacokinetics, Biodistribution and Mechanism(s) of Intrarenal Transport
| dc.contributor.advisor | Tam, Vincent H. | |
| dc.contributor.committeeMember | Chow, Diana Shu-Lian | |
| dc.contributor.committeeMember | Hu, Ming | |
| dc.contributor.committeeMember | Eriksen, Jason | |
| dc.contributor.committeeMember | Sherer, Jeffrey T. | |
| dc.contributor.committeeMember | Truong, Luan D. | |
| dc.creator | Manchandani, Pooja | |
| dc.date.accessioned | 2019-11-17T21:54:31Z | |
| dc.date.available | 2019-11-17T21:54:31Z | |
| dc.date.created | December 2016 | |
| dc.date.issued | 2016-12 | |
| dc.date.submitted | December 2016 | |
| dc.date.updated | 2019-11-17T21:54:31Z | |
| dc.description.abstract | Objectives: Despite dose-limiting nephrotoxic potentials, polymyxin B has re-emerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic and nephrotoxic properties of polymyxin B are still not thoroughly understood. The objectives of this study were to provide additional insights to the overall biodistribution and disposition of polymyxin B; to evaluate the impact of renal polymyxin B exposure on nephrotoxicity; to delineate the underlying transport mechanism(s) responsible for the intrarenal drug accumulation. Methods: A comparative pharmacokinetic profile of various polymyxin B components following intravenous administration was derived in rats. The overall drug biodistribution in various organs (brain, heart, lungs, liver, spleen, kidneys and skeletal muscle) was assessed. Intrarenal distribution of polymyxin B was evaluated at the cellular level. Drug disposition was quantified in rat urine/ bile. Renal drug accumulation was assessed at different polymyxin B dosing levels, and the onset of polymyxin B-induced nephrotoxicity was correlated to the renal drug exposure. The role of megalin, a renal endocytic receptor was evaluated in the renal accumulation of polymyxin B. Results: The pharmacokinetic profiles of individual polymyxin B components were comparable. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. Within kidneys, the highest drug accumulation was observed in the proximal tubular cells. Less than 5% of administered dose (or pharmacologically active metabolites, if any) were recovered in the urine over 48 h, but all four major polymyxin B components were detected in the bile over 4 h. The higher daily dose of polymyxin B resulted in greater renal accumulation. The onset of nephrotoxicity was correlated to the daily dose of polymyxin B. The megalin-mediated renal uptake of polymyxin B could be disrupted. Conclusions: The individual components of polymyxin B demonstrate similar pharmacokinetics. The biodistribution findings corroborate our previous results that polymyxin B is highly accumulated in the kidneys, but the elimination is likely via a non-renal route. Biliary excretion could be one of the possible routes of polymyxin B elimination, which should be further explored. The onset of polymyxin B-induced nephrotoxicity is correlated to the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Portions of this document appear in: Manchandani, Pooja, Jian Zhou, Kimberly R. Ledesma, Luan D. Truong, Diana S-L. Chow, Jason L. Eriksen, and Vincent H. Tam. "Characterization of polymyxin B biodistribution and disposition in an animal model." Antimicrobial agents and chemotherapy 60, no. 2 (2016): 1029-1034. And in: Manchandani, Pooja, Yanina Dubrovskaya, Song Gao, and Vincent H. Tam. "Comparative pharmacokinetic profiling of different polymyxin B components." Antimicrobial agents and chemotherapy 60, no. 11 (2016): 6980-6982. | |
| dc.identifier.uri | https://hdl.handle.net/10657/5445 | |
| 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. UH Libraries has secured permission to reproduce any and all previously published materials contained in the work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Polymyxin B | |
| dc.subject | Pharmacokinetics | |
| dc.subject | Biodistribution | |
| dc.subject | Megalin | |
| dc.subject | Nephrotoxicity | |
| dc.title | Revisiting Polymyxin B: Pharmacokinetics, Biodistribution and Mechanism(s) of Intrarenal Transport | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences | |
| thesis.degree.discipline | Pharmaceutics | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |