Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde: pharmacokinetic modeling for estimation of intracellular levels

Ifosfamide (IF) improves survival in children with solid tumors but causes a high rate of nephrotoxicity. We hypothesized that this is caused by an oxidative metabolite of IF, chloroacetaldehyde, which is produced locally by the cells of the renal tubule (RT). For this hypothesis to be viable, one must document that chloroacetaldehyde concentrations in the RT cell are consistent with levels shown to cause nephrotoxicity in experimental systems. Using pharmacokinetic modeling of experimental data, we show that the median level of chloroacetaldehyde in RT cells is 80 micromol/L, ranging from 35 to 320 micromol/L. These concentrations are consistent with levels shown experimentally to cause functional and structural RT damage and lends validity to the hypothesis that local renal production of chloroacetaldehyde causes nephrotoxicity.