Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound

Abstract

Zoledronic acid, a highly potent nitrogen-containing bisphosphonate used for the treatment of pathological bone loss, is excreted unmetabolized via the kidney if not bound to the bone. In cancer patients receiving high doses of the compound renal excretion may be associated with acute tubular necrosis. The question of how zoledronic acid is internalized by renal tubular cells has not been answered until now. In the current work, using a primary human tubular cell culture system, the pathway of cellular uptake of zoledronic acid (fluorescently/radiolabeled) and its cytotoxicity were investigated. Previous studies in our laboratory have shown that this primary cell culture model consistently mimics the physiological characteristics of molecular uptake/transport of the epithelium in vivo. Zoledronic acid was found to be taken up by tubular cells via fluid-phase-endocytosis (from apical and basolateral side) as evidenced by its co-localization with dextran. Cellular uptake and the resulting intracellular level was twice as high from the apical side compared to the basolateral side. Furthermore, the intracellular zoledronic acid level was found to be dependent on the administered concentration and not saturable. Cytotoxic effects however, were only seen at higher administration doses and/or after longer incubation times. Although zoledronic acid is taken up by tubular cells, no net tubular transport could be measured. It is concluded that fluid-phase-endocytosis of zoledronic acid and cellular accumulation at high doses may be responsible for the acute tubular necrosis observed in some cancer patients receiving high doses of the compound.

Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity

“…Unbound zoledronate is excreted unmetabolized through the kidney (Markowitz et al 2003 ; Munier et al 2005 ). Despite the clinical importance of zoledronate in several therapeutic areas, numerous cases of zoledronate-associated nephrotoxicity have been reported, which are shown to lead to renal failure, acute tubular necrosis and renal fibrosis characterized by tubular cell degeneration, loss of brush border, and apoptosis, when given intravenously (Chang et al 2003 ; Markowitz et al 2003 ; McKay et al 2014 ; Munier et al 2005 ; Ott 2012 ; Papapetrou 2009 ; Perazella and Markowitz 2008 ; Verhulst et al 2015 ). The mechanisms of zoledronate-induced kidney toxicity are thought to be similar to its pharmacological effects in osteoclasts.…”

Early onset acute tubular necrosis following single infusion of zoledronate

“…A recent paper presented evidence that zoledronate is internalized by renal tubular cells via the process of fluid phase endocytosis. The resulting intracellular accumulation of zoledronate may act as an epithelial toxin inducing tubular cytotoxicity (9). The majority of cases of zoledronate associated toxic ATN reported to date had multiple myeloma or other cancers and received varying types of chemotherapy.…”

Inhibitory actions by ibandronate sodium, a nitrogen-containing bisphosphonate, on calcium-activated potassium channels in Madin–Darby canine kidney cells

“…The estimated peak of plasma Iban concentration has been reported to reach 5 × 10 3 ng/ml (around 14 μM) [21] . Additionally, the bisphosphonates like Iban can be virtually taken or even accumulated in renal tubular cells through the process of fluid phase endocytosis [3] , [38] . Consequently, the observed effects by Iban on BK Ca channels tend to develop during the open state of the channel and may occur at the range of the concentrations achievable in humans.…”

“…These compounds are not metabolized in either man or animal, and consequently, they are the active, parent compounds. The principal route of their elimination results from renal excretion [15] and these compounds can accumulate in the kidney during therapy [3] , [38] . It is important to note that potential nephrotoxicity has been observed in patients receiving high-dose bisphosphonate therapy, particularly when administrated by rapid intravenous administration [2] , [18] , [22] , [27] , [28] , [29] , [32] .…”