The N-dechloroethylation of ifosfamide: using stereochemistry to obtain an accurate picture of a clinically relevant metabolic pathway

Abstract:  The cumulative urinary excretions of the enantiomers of ifosfamide [(R)-IFF, (S)-IFF)] and their 2-N-dechloroethylated (2-DCE-IFF) and 3-N-dechloroethylated (3-DCE-IFF) metabolites were determined in 11 adult cancer patients who received a single 3-h infusion of IFF (3 g/m²) with mesna uroprotection. The urine samples were analyzed for the compounds of interest using an enantioselective gas chromatographic- mass spectrometric assay. The results indicated an enantioselective excretion of the parent and N-dechloroethylated metabolites: the urinary recovery of (R)-IFF was significantly greater than that of (S)-IFF (1.73 0.45 vs 1.430.41 mmol, P<0.0001); the excretion of (S)-2-DCE-IFF (0.750.53 mmol) was greater than that of (R)-2-DCE-IFF (0.42 0.22 mmol, P=0.071) while the excretion of (R)-3-DCE-IFF (1.64 0.76 mmol) was greater than that of (S)-3-DCE-IFF (0.770.59 mmol, P=0.012). The study also revealed two distinct metabolic patterns in which the urinary recoveries of (R)-2-DCE-IFF and (R)-3-DCE-IFF were linked as were those of (S)-2-DCE-IFF and (S)-3-DCE-IFF. The results suggest that at least two enzymes are involved in the N-dechloroethylation of IFF. The data also demonstrate the importance of following the metabolic fate of (R)-IFF and (S)-IFF and of determining the relative urinary excretion of all dechloroethylated metabolites.