Stereoselective pharmacokinetics of ifosfamide in male and female rats.

The stereoselective pharmacokinetics of ifosfamide (IF) were investigated in male and female Sprague-Dawley rats. Following intravenous administration of IF deuterium-labeled pseudoracemates into rats at 40 mg/kg, IF enantiomers and their metabolites, 4-hydroxyIF (HOIF), N2-dechloroethylIF (N2D), N3-dechloroethylIF (N3D), and isophosphoramide mustard (IPM) were quantitated in plasma and urine using gas chromatographic-mass spectrometry techniques with appropriately deuterium-labeled analogs as the internal standards. In addition, the intrinsic clearances of IF isomers in rat liver microsomes were estimated by the in vitro metabolism study. Following drug administration in male rats, (R)-IF exhibited a lower area under the curve value and a shorter half-life of 34.2 minutes than (S)-IF, which gave a half-life of 41.8 minutes. In female rats, the half-lives of (R)- and (S)-IF were found to be 62.1 and 75.1 minutes, respectively, significantly longer than those in male rats. No change in volume of distribution or renal clearance for IF enantiomers in all rats was observed, and the protein binding value was low, with no enantioselectivity. Both in vitro and in vivo studies showed that metabolism of (R)-IF proceeded in favor of the 4-hydroxylation pathway, whereas (S)-IF preferentially underwent N2- and N3-dechloroethylation. The observed stereoselectivity and gender difference in pharmacokinetics of IF in the rat are mainly attributed to its stereoselective metabolism.