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Differential in vitro hepatic and intestinal metabolism of ifosfamide in the rat.

1. Metabolism of ifosfamide (IF) in intestinal and hepatic microsomes has been investigated in the rat. The generation of three primary metabolites, 4-hydroxyifosfamide (HOIF), N2-dechloroethylifosfamide (N2D) and N3-dechloroethylifosfamide (N3D), was followed. 2. Microflora in rat small intestine showed no metabolic activity towards IF. The overall metabolic activity was higher in the hepatic microsomes than in the intestinal microsomes, and the hydroxylation pathway accounted for 53.6% of total IF metabolism in the hepatic microsomes. In contrast, hydroxylation of IF in intestinal microsomes was only 9.8% of the total monitored metabolic activity and N3-dechloroethylation of IF was a major pathway, constituting 73.0% of the monitored activity. 3. In summary, the intestinal metabolism of IF was demonstrated for the first time and these in vitro data indicate that the intestinal metabolism of IF could contribute significantly to the overall first-pass metabolism.