941 Hydrolysis of ifosfamide to chloroethylamine

Abstract

We have recently described the formation of Chloroethylamine (CEA) and 1,3-Oxazolidine-2-one (OXAZ) in humans following Ifosfamide (IF) administration † , and have now determined these levels in the plasma of 12 patients, ten of whom received 500 mg oral (o) IF, and two 3 g m−2 intravenous (iv) IF. GC-MS was used to measure IF, CEA and OXAZ. Mean CEA/IF peak ratios were 0.072 (o) and 0.49 (iv) and corresponding values for OXAZ/IF 0.011 (o) and 0.029 (iv). As only equimolar quantities of CEA and OXAZ can be formed from isophosphoramide mustard, the relatively high amount of CEA after iv dosing is generated directly by the hydrolysis of IF. This was confirmed by the detection of 2-chloroethyl-3-hydroxypropylamine, its phosphoric acid ester, and CEA, on incubation of IF solution in vitro at 37 °C. The rate of formation of CEA was consistent with pseudo-first order reaction kinetics. We conclude that significant hydrolysis of IF occurs, both in vivo and in vitro, at 37 °C.