Role of renal drug exposure in polymyxin B-induced nephrotoxicity

P Manchandani, J Zhou, JT Babic… - Antimicrobial agents …, 2017 - Am Soc Microbiol
P Manchandani, J Zhou, JT Babic, KR Ledesma, LD Truong, VH Tam
Antimicrobial agents and chemotherapy, 2017Am Soc Microbiol
Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of
therapy against multidrug-resistant Gram-negative bacterial infections. However, the
handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of
this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and
to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250
g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 …
Abstract
Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 ± 0.4 μg/g, 9.9 ± 1.5 μg/g, and 21.7 ± 4.8 μg/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with 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.
American Society for Microbiology