1. Metabolism of ifosfamide (IF) in intestinal and hepatic microsomes
has been investigated in the rat. The generation of three primary meta
bolites, 4-hydroxyifosfamide (HOIF), N2-dechloroethylifosfamide (N2D)
and N3-dechloroethylifosfamide (N3D), was followed. 2. Microflora in r
at small intestine showed no metabolic activity towards IF. The overal
l 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, hyd
roxylation of IF in intestinal microsomes was only 9.8 % of the total
monitored metabolic activity and N3-dechloroethylation of IF was a maj
or pathway, constituting 73.0 % of the monitored activity. 3. In summa
ry, the intestinal metabolism of IF was demonstrated for the first tim
e and these in vitro data indicate that the intestinal metabolism of I
F could contribute significantly to the overall first-pass metabolism.