Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6 |
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| Authors: | H. Lu J. J. Wang K. K. Chan P. A. Philip |
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| Affiliation: | 1. Colleges of Pharmacy and Medicine and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA;2. Division of Hematology and Oncology, Wayne State University, Detroit, MI, USA |
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| Abstract: | 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. |
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| Keywords: | Ifosfamide 4-hydroxylation N2- and N3-dechloroethylation CYP3A4 CYP2B6 GC/MS |
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