Renal biotransformation of ifosfamide to potentially nephrotoxic metabolites

C. Woodland, S. Ito, G. Koren

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Ifosfamide use in cancer chemotherapy is associated with nephrotoxicity while cyclophosphamide use is not. Ifosfamide and cyclophosphamide are prodrugs that differ by the position of a chloroethyl group. The two drugs are biotransformed similarly, however, in order to achieve equimolar concentrations of the alkylating mustard species, patients are generally given approximately 3-fold higher doses of ifosfamide. This results in the production of up to 100-fold higher concentrations of the chloroacetaldehyde metabolite from ifosfamide as compared to cyclophosphamide. Cell culture studies suggest that this metabolite is more nephrotoxic than the parent ifosfamide compound. However, chloroacetaldehyde is very unstable and metabolite produced in the liver may not even reach the kidney. Therefore, we hypothesized that a local production of chloroacetaldehyde is the cause of nephrotoxicity. In human liver, ifosfamide is metabolized to chloroacetaldehyde by CYP3A. Human kidney also contains CYP3A. We incubated pig kidney microsomes with ifosfamide and used an HPLC assay to detect the stable 2- and 3-dechloroethylifosfamide metabolites that are co-produced with chloroacetaldehyde. The dechloroethyl metabolites were produced under cytochrome P450-mediated reaction conditions. Metabolite production was reduced in the presence of inhibitors of CYP3A. Our findings suggest that the kidney has the capacity to biotransform ifosfamide to potentially toxic metabolites. Variations in CYP3A expression may explain why some individuals are more susceptible to ifosfamide nephrotoxicity.

Original languageEnglish
Pages (from-to)A767
JournalFASEB Journal
Issue number5
StatePublished - 20 Mar 1998
Externally publishedYes


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