Anticancer treatment with
ifosfamide but not with its structural isomer
cyclophosphamide is associated with development of
renal Fanconi syndrome leading to diminished growth in children and bone problems in adults. Since both cytotoxics share the same principal metabolites, we investigated whether a specific renal uptake of
ifosfamide is the basis for this differential effect. First we studied the interaction of these cytotoxics using cells transfected with organic
anion or
cation transporters and freshly isolated murine and human proximal tubules with appropriate tracers. Next we determined changes in membrane voltage in proximal tubular cells to understand their differentiated nephrotoxicity.
Ifosfamide but not
cyclophosphamide was significantly transported into cells expressing human
organic cation transporter 2 (hOCT2) while both did not interact with
organic anion transporters. This points toward a specific interaction of
ifosfamide with hOCT2, which is the main OCT
isoform in human kidney. In isolated human proximal tubules
ifosfamide also interacted with organic
cation transport. This interaction was also seen in isolated mouse proximal tubules; however, it was absent in tubules from OCT-deficient mice, illustrating the biological importance of this selective transport.
Ifosfamide decreased the viability of cells expressing hOCT2, but not that of control cells. Coadministration of
cimetidine, a known competitive substrate of hOCT2, completely prevented this
ifosfamide-induced toxicity. Finally,
ifosfamide but not
cyclophosphamide depolarized proximal tubular cells. We propose that the nephrotoxicity of
ifosfamide is due to its selective uptake by hOCT2 into renal proximal tubular cells, and that coadministration of
cimetidine may be used to prevent
ifosfamide-induced nephrotoxicity.