The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N2- and N3-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N2- and N3-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N2-dechloroethylIFA (N2D) and (R)-N3-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.
The objective of this study was to study the enantiomer-enantiomer interaction of ifosfamide (IFA) in a rat model. Following intravenous administration of individual IFA enantiomers or pseudo-racemates to male Sprague-Dawley rats, two enantiomers and their metabolites, 4-hydroxyIF (HOIF), N2-dechloroethylIF (N2D), N3-dechloroethylIF (N3D), and isophosphoramide (IPM), were quantified using gas chromatography/mass spectrometry (GC/MS) and isotope dilution techniques. In addition, the mutual inhibition in the metabolism between two stereoisomers was also investigated in vitro using rat liver microsomes. Pharmacokinetic parameters were similar between (R)-IFA and (S)-IFA when individual enantiomers were intravenously administered to rats separately. However, in the rats administered with the IFA racemate, half-life, mean residence time (MRT), and area under the concentration-time curve (AUC) values of (S)-IFA were significantly increased with total body clearance (CLT) being decreased. No significant difference in volumes of distribution (Vss), and renal clearance (CLr) and blood cell partition was observed between two enantiomers regardless of (R)-IFA and (S)-IFA being administered separately or in combination as a racemate. The results from the in vitro metabolism and inhibition experiment suggested that each IFA enantiomer inhibited the metabolism of its antipode in a competitive manner. It is concluded that the enantiomeric interaction of IFA mainly occurred in the process of metabolism with (S)-IFA being affected to a larger extent.
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