Renal clearance of ifosfamide

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide. This medication is activated by the hepatic cytochrome p450 system with potentially toxic metabolites produced through both ring hydroxylation and chloroethyl side chain oxidation pathways. Using an isolated perfused rat kidney preparation, we examined the possibility that renal metabolism of ifosfamide also occurs. Renal function before and after addition of ifosfamide to perfusate was not significantly different. After addition of ifosfamike to the perfusate, the metabolites N2- dechloroethylifosfamide, N3-dechloroethylifosfamide, and isophasphoramide mustard were recovered from urine and renal venous effluent. These results provide the first demonstration of ifosfamide metabolism by the kidney and suggest the possibility that intratenal metabolism may contribute to nephrotoxicity.