Stereoselective pharmacokinetics of ifosfamide in male and female rats
Journal Title: The AAPS Journal - Year 2000, Vol 2, Issue 2
Abstract
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.
Authors and Affiliations
Jeff J. Wang, Hong Lu, Kenneth K. Chan
Keywords
Related Articles
- EP ID EP682090
- DOI 10.1208/ps020217
- Views 302
- Downloads 0
Role of the breast cancer resistance protein (ABCG2) in drug transport
The 72-kDa breast cancer resistance protein (BCRP) is the second member of the subfamily G of the human ATP binding cassette (ABC) transporter superfamily and thus also designated as ABCG2. Unlike P-glycoprotein and MRP1...
Development of a Method That Eliminates False-Positive Results due to Nerve Growth Factor Interference in the Assessment of Fulranumab Immunogenicity
Fulranumab, a human IgG2 monoclonal antibody that neutralizes nerve growth factor (NGF), is currently in development for the treatment of pain. Our initial immunogenicity test method was found to be prone to NGF interfer...
Neuro-fuzzy Models as an IVIVR Tool and Their Applicability in Generic Drug Development
The online version of this article (doi:10.1208/s12248-014-9569-8) contains supplementary material, which is available to authorized users.
Commentary: Drug hypersensitivity—Where do we stand?
GATG Dendrimers and PEGylated Block Copolymers: from Synthesis to Bioapplications
Dendrimers are synthetic macromolecules composed of repetitive layers of branching units that emerge from a central core. They are characterized by a tunable size and precise number of peripheral groups which determine t...