Stereoselective pharmacokinetics of ifosfamide and its 2- and 3-N-dechloroethylated metabolites in female cancer patients.
The pharmacokinetics of the R and S enantiomers of ifosfamide (IFF) and 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 infusion of (R,S)-IFF (3 g/m2) with mesna uroprotection. An enantioselective gas chromatographic-mass spectrometric (GC-MS) assay was used to determine the concentrations in plasma and urine. The AUCs of (R)-IFF were significantly larger than those of (S)-IFF (2480 +/- 200 vs 1960 +/- 150 microM.h). The terminal half-lives (7.57 +/- 0.99 h) and mean residence times (11.17 +/- 1.10 h) of (R)-IFF were significantly longer than those of (S)-IFF, 6.03 +/- 0.82 h and 9.37 +/- 0.88 h, respectively. The mean volume of distribution at steady rate of (R)-IFF (25.68 +/- 0.80 l/m2) was slightly smaller than that of (S)-IFF (27.35 +/- 0.89 l/m2). While the renal clearances of (R)-IFF and (S)-IFF were similar, the nonrenal clearance was significantly lower for (R)-IFF (30.20 +/- 2.70 vs 41.40 +/- 3.55 ml/m2 per min) as was total clearance (41.52 +/- 2.90 vs 52.37 +/- 3.75 ml/m(2) per min). The AUC values for all 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 enantioselective difference in IFF elimination can be partially explained by differences in N-dechloroethylation.
Granvil
C P
CP
Département de Pharmacologie, Université de Montréal, Quebéc, Canada.
Ducharme
J
J
Leyland-Jones
B
B
Trudeau
M
M
Wainer
I W
IW
D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism* / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D010386:Pelvic Neoplasms / Q000188:drug therapy*; D013237:Stereoisomerism
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide