Metabolism of Cyclophosphamide by CYP2B6 and Associated Polymorphisms
Abbott, Joshua M.
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Cyclophosphamide (CPA) is one of the most widely used drugs in cancer treatment, yet, there is considerable interpatient variability with regards to efficacy and toxicity with CPA treatment. This interpatient variability is not well understood. CPA is an oxazaphosphorine prodrug, requiring bioactivation by a cytochrome P450. Cytochrome P450 2B6 (CYP2B6) is the major P450 involved in CPA activation. CYP2B6 is known to be highly polymorphic, and these polymorphisms have been demonstrated to affect the metabolism of other known CYP2B6 substrates such as bupropion and efavirenz. We hypothesized that CYP2B6 polymorphisms have varying ability to metabolize CPA, resulting in varying amounts of activated CPA. This is a potential cause for the efficacy and toxicity discrepancies with regard to CPA treatment. We have refined and examined two different assays for the measurement of a cyclophosphamide metabolite, and used dansyl hydrazine to derivatize a fluorescent product. We also evaluated the metabolism of CPA by the wild type CYP2B6 and its polymorphisms CYP2B6*4, CYP2B6*5, CYP2B6*6, CYP2B6*7, CYP2B6*8, and CYP2B6*9. We found that there were no significant differences in the metabolic activity of CYP2B6 polymorphisms compared to wild type.