STEREOSELECTIVE PHARMACOKINETICS OF IFOSFAMIDE AND ITS 2-N-DECHLOROETHYLATED AND 3-N-DECHLOROETHYLATED METABOLITES IN FEMALE CANCER-PATIENTS

The pharmacokinetics of the R and S enantiomers of ifosfamide (IFF) an d of its 2- and 3-N-dechloroethylated metabolites (2-DCE-IFF and 3-DCE -IFF) were investigated in 14 cancer patients treated with a 3-h infus ion of (R,S)-IFF (3 g/m(2)) with mesna uroprotection. An enantioselect ive gas chromatographic-mass spectrometric (GC-MS) assay was used to d etermine the concentrations in plasma and urine. The AUCs of (R)-IFF w ere significantly larger than those of (S)-IFF (2480 +/- 200 vs 1960 /- 150 mu M.h). The terminal half-lives (7.57 +/- 0.99 h) and mean res idence times (11.17 +/- 1.10 h) of (R)-IFF were significantly longer t han those of(S)-IFF, 6.03 +/- 0.82 h and 9.37 +/- 0.88 h, respectively . The mean volume of distribution at steady state of (R)-IFF (25.68 +/ - 0.80 l/m(2)) was slightly smaller than that of(S)-IFF (27.35 +/- 0.8 9 l/m(2)). While the renal clearances of (R)-IFF and (S)-IFF were simi lar, the nonrenal clearance was significantly lower for (R)-IFF (30.20 +/- 2.70 vs 41.40 +/- 3.55 ml/m(2) per min) as was total clearance (4 1.52 +/- 2.90 vs 52.37 +/- 3.75 ml/m(2) per min). The AUC values for a ll of the DCE metabolites from (S)-IFF were significantly greater than those from (R)-IFF with 47% of the measured AUC accounted for by DCE from (S)-IFF compared to only 20% for (R)-IFF. Therefore, the enantios elective difference in IFF elimination can be partially explained by d ifferences in N-dechloroethylation.