THE N-DECHLOROETHYLATION OF IFOSFAMIDE - USING STEREOCHEMISTRY OBTAINAN ACCURATE PICTURE OF A CLINICALLY RELEVANT METABOLIC PATHWAY

The cumulative urinary excretions of the enantiomers of ifosfamide [(R )-IFF, (S)-IFF)] and their 2-N-dechloroethylated (2-DCE-IFF) and 3-N-d echloroethylated (3-DCE-IFF) metabolites were determined in 11 adult c ancer patients who received a single 3-h infusion of IFF (3 g/m(2)) wi th mesna uroprotection. The urine samples were analyzed for the compou nds of interest using an enantioselective gas chromatographic-mass spe ctrometric assay. The results indicated an enantioselective excretion of the parent and N-dechloroethylated metabolites: the urinary recover y of (R)-IFF was significantly greater than that of (S)-IFF (1.73 +/- 0.45 vs 1.43 +/- 0.41 mmol, P < 0.0001); the excretion of (S)-2-DCE-IF F (0.75 +/- 0.53 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 (0.77 +/- 0.59 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 wer e 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-dechloroethyl ation of IFF. The data also demonstrate the importance of following th e metabolic fate of(R)-IFF and (S)-IFF and of determining the relative urinary excretion of all dechloroethylated metabolites.