title: Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model.
abstract: Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Manchandani
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Ledesma
authors.affiliation: The Methodist Hospital Research Institute, Houston, Texas, USA.
authors.forename: Luan D
authors.initials: LD
authors.lastname: Truong
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Diana S-L
authors.initials: DS
authors.lastname: Chow
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Eriksen
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, Texas, USA vtam@uh.edu.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D011112:Polymyxin B / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B