Revisiting Polymyxin B: Pharmacokinetics, Biodistribution and Mechanism(s) of Intrarenal Transport

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.