Metabolism of Cyclophosphamide by CYP2B6 and Associated Polymorphisms
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Authors
Abbott, Joshua M.
Issue Date
2012
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
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.
Description
vii, 21p.
Citation
Publisher
Kalamazoo College
License
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