title: New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2.
abstract: 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.
authors.affiliation: Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciarimboli
authors.forename: Svenja Kristina
authors.initials: SK
authors.lastname: Holle
authors.forename: Beate
authors.initials: B
authors.lastname: Vollenbröcker
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Hagos
authors.forename: Stefan
authors.initials: S
authors.lastname: Reuter
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.forename: Stefan
authors.initials: S
authors.lastname: Bierer
authors.forename: Edwin
authors.initials: E
authors.lastname: Herrmann
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Rainer
authors.initials: R
authors.lastname: Rossi
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schlatter
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002927:Cimetidine / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000493:pharmacokinetics* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2
chemical_list: D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D002927:Cimetidine; D007069:Ifosfamide