Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

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 Ϯ 0.4 g/g, 9.9 Ϯ 1.5 g/g, and 21.7 Ϯ 4.8 g/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. KEYWORDS Polymyxin B, renal drug concentration, megalin, polymyxins T here is a renewed interest in the clinical use of polymyxins due to the increased prevalence of infections caused by multidrug-resistant Gram-negative bacteria (1). Many currently available antibiotics are no longer effective against these resistant bacterial strains. Additionally, the situation is further exacerbated by the limited number of new antibacterial agents in the advanced drug development pipeline. Consequently, the polymyxins have emerged as the last treatment resort against these life-threatening infections.Polymyxins (polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics which were available for clinical use in the 1950s. However, the clinical use of polymyxins was considerably reduced in the early 1970s due to concerns about nephrotoxicity (2-4). Despite being available for decades, the correlation between the pharmacokinetics and toxicodynamic profiles of polymyxin B is still not thoroughly understood. This knowledge gap often hinders the optimal clinical use of polymyxin B. There is evidence suggesting that polymyxin B is not eliminated through the renal route (5, 6). However, pharmacokinetic studies have reported preferential accumulation and prolonged residence of polymyxin B in rat kidneys (7,8). Several studies have also reported a daily dose of polymyxin B as an independent risk factor associated with...

A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion

“…However, these hypotheses did not improve the fitting or parameters were not identifiable. Moreover, the latter assumption, besides the modelling results, was also in contradiction with the results of previous studies showing in vivo that when the reabsorption of colistin or polymyxin B in renal tubules was inhibited, the renal exposures was reduced considerably but the kinetic profiles in plasma remained unaltered (10,61). The fact that total clearance of polymyxin remained unchanged, whether the reabsorption was inhibited or not, suggested that polymyxin was eliminated within the kidney, either excreted in urine or metabolized, but did not go back to the systemic circulation.…”

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity

“…These data are in agreement with the pharmacokinetics of PMB in humans, where the renal clearance of PMB is only a small fraction of the expected filtration clearance, indicating that PMB undergoes extensive tubular reabsorption (10). Accumulation of PMB in proximal tubule epithelial cells (PTECs) can likely be attributed to the negative charge of the brush border, the high expression of transporters and receptors involved in reabsorption of solutes from the ultrafiltrate, or a combination of the two (11,12). Consequently, the toxicity of PMB toward PTECs may be driven by its polycationic nature.…”

Gelofusine Ameliorates Colistin-Induced Nephrotoxicity

“…Third, because gelofusine consists of a heterogeneous mixture of both cationic and anionic peptides of various sizes and structures, it has been suggested to interfere with all four of the charged amino acid repeats on the megalin receptor, thereby effectively blocking the renal reabsorption of a variety of molecules (31). Taken together, this all sits well with the available evidence which points to a role for megalin in the renal reabsorption of polymyxin B and colistin (10,11,13). Therefore, it is tenable to imagine that gelofusine competitively inhibits the carrier-mediated renal reabsorption of colistin and may also modify the endosomal/lysosomal trafficking of colistin (32).…”

“…The result is an extensive accumulation of polymyxin in tubular cells, which undoubtedly contributes significantly to polymyxin-induced renal tubular damage (6,9). Available evidence points to the involvement of megalin and PEPT2 carrier systems in the renal reabsorption of polymyxins; these systems are known to scavenge other peptides and proteins from tubular urine (10)(11)(12)(13)(14).…”