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Wang D, Wang H. Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors. Acta Pharm Sin B. 2012;2(2)doi: 10.1016/j.apsb.2012.02.004.
Wang, D., & Wang, H. (2012). Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors. Acta pharmaceutica Sinica. B, 2(2), . https://doi.org/10.1016/j.apsb.2012.02.004
Wang, Duan, and Wang, Hongbing. "Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors." Acta pharmaceutica Sinica. B vol. 2,2 (2012). doi: https://doi.org/10.1016/j.apsb.2012.02.004
Wang D, Wang H. Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors. Acta Pharm Sin B. 2012 Apr 01;2(2). doi: 10.1016/j.apsb.2012.02.004. PMID: 24349963; PMCID: PMC3860377.
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Acta Pharm Sin B. 2012 Apr 01;2(2). doi: 10.1016/j.apsb.2012.02.004.

Oxazaphosphorine bioactivation and detoxification The role of xenobiotic receptors.

Acta pharmaceutica Sinica. B

Duan Wang, Hongbing Wang

Affiliations

  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore MD 21201, USA.

PMID: 24349963 PMCID: PMC3860377 DOI: 10.1016/j.apsb.2012.02.004

Abstract

Oxazaphosphorines, with the most representative members including cyclophosphamide, ifosfamide, and trofosfamide, constitute a class of alkylating agents that have a broad spectrum of anticancer activity against many malignant ailments including both solid tumors such as breast cancer and hematological malignancies such as leukemia and lymphoma. Most oxazaphosphorines are prodrugs that require hepatic cytochrome P450 enzymes to generate active alkylating moieties before manifesting their chemotherapeutic effects. Meanwhile, oxazaphosphorines can also be transformed into non-therapeutic byproducts by various drug-metabolizing enzymes. Clinically, oxazaphosphorines are often administered in combination with other chemotherapeutics in adjuvant treatments. As such, the therapeutic efficacy, off-target toxicity, and unintentional drug-drug interactions of oxazaphosphorines have been long-lasting clinical concerns and heightened focuses of scientific literatures. Recent evidence suggests that xenobiotic receptors may play important roles in regulating the metabolism and clearance of oxazaphosphorines. Drugs as modulators of xenobiotic receptors can affect the therapeutic efficacy, cytotoxicity, and pharmacokinetics of coadministered oxazaphosphorines, providing a new molecular mechanism of drug-drug interactions. Here, we review current advances regarding the influence of xenobiotic receptors, particularly, the constitutive androstane receptor, the pregnane X receptor and the aryl hydrocarbon receptor, on the bioactivation and detoxification of oxazaphosphorines, with a focus on cyclophosphamide and ifosfamide.

Keywords: CAR; CYP2B6; PXR; cyclophosphamide; ifosfamide; oxazaphosphorine

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