Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expressed cytochromes P450.

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Chen CS, Jounaidi Y, Waxman DJ

Enantioselective metabolism and cytotoxicity of R-ifosfamide and S-ifosfamide by tumor cell-expressed cytochromes P450.

Drug Metab Dispos. 2005 Sep;33(9):1261-7. Epub 2005 May 26.

PubMed ID

15919850 [ View in PubMed

]

Abstract

The anticancer prodrug ifosfamide (IFA) contains a chiral phosphorous atom and is administered in the clinic as a racemic mixture of R-IFA and S-IFA. Hepatic cytochrome P450 (P450) enzymes exhibit enantioselective preferences in the metabolism of R-IFA and S-IFA; however, the impact of this selectivity on P450-dependent anticancer activity is not known. Presently, the metabolism and cytotoxicity of R-IFA and S-IFA were determined in 9L gliosarcoma and Chinese hamster ovary tumor cells expressing an IFA-activating P450 enzyme and by in vitro steady-state kinetic analysis using cDNA-expressed P450 enzymes. Tumor cells expressing P450 enzyme CYP3A4 were the most sensitive to R-IFA cytotoxicity, whereas tumor cells expressing CYP2B1 or CYP2B6 were most sensitive to cyclophosphamide (CPA), an isomer of IFA. Correspondingly, CYP3A4-expressing cells and cDNA-expressed CYP3A4 metabolized R-IFA to yield the active, 4-hydroxylated metabolite at a 2- to 3-fold higher rate than they metabolized S-IFA or CPA. CYP2B cells and cDNA-expressed CYP2B enzymes metabolized CPA almost exclusively by 4-hydroxylation, whereas R-IFA and S-IFA were substantially converted to inactive, N-dechloroethylated metabolites. Further investigation revealed that CYP3A1, a rat enzyme, exhibited superior kinetic properties compared with the human enzyme CYP3A4, with R-IFA and S-IFA both metabolized with high catalytic efficiency by 4-hydroxylation and with a K(m) value of 200 microM, approximately 5-fold lower than CYP3A4. Based on these kinetic parameters and metabolic profiles, R-IFA is expected to exert greater anticancer activity than S-IFA or CPA against tumors that express CYP3A enzymes, whereas tumors expressing CYP2B enzymes may be more sensitive to CPA treatment.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Ifosfamide	Cytochrome P450 2B6	Protein	Humans	Unknown	Substrate	Details
Ifosfamide	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details