Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites

Nephrotoxicity is a limiting factor in the use of ifosfamide in children. D espite the co-administration of uroprotective agents such as sodium 2-merca ptoethanesulfonate (mesna), ifosfamide chemotherapy is associated with neph ropathy characterized by glomerular toxicity and Fanconi syndrome in many c hildren treated with this drug. This is in distinction to cyclophosphamide, an analogue which differs solely by the position of a chloroethyl group, a nd which is not associated with nephrotoxicity. We hypothesized that ifosfa mide is metabolized by cytochrome P450 (CYP) enzymes located in the renal t ubular cell to the toxic metabolite chloroacetaldehyde; and, that the highe r production of chloroacetaldehyde from ifosfamide than from cyclophosphami de explains the clinical differences in nephrotoxicity. We found that in bo th pig renal cortical microsomes and whole human kidney microsomes incubate d with 1 mM ifosfamide for 3 hr, 2 and 3 dechloroethylifosfamide (DCEI) wer e produced. Our study provides evidence that porcine and human kidney micro somes are capable of biotransforming ifosfamide to DCEI metabolites that ar e produced in equimolar amounts with chloroacetaldehyde, indicating that ch loroacetaldehyde is locally produced by renal cells as a possible mechanism for nephrotoxicity. (C) 2000 Elsevier Science Inc. All rights reserved.