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    IN VITRO HEPATIC OXIDATIVE BIOTRANSFORMATION OF TRIMETHOPRIM

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    Issue Date
    2015-05-31
    Author
    Goldman, Jennifer Lynn
    Publisher
    University of Kansas
    Format
    34 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Preventive Medicine and Public Health
    Rights
    Copyright held by the author.
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    Abstract
    Introduction: Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly used antibiotic often associated with idiosyncratic adverse drug reactions (IADRs). Historically, bioactivation of SMX to a reactive intermediate has been implicated in IADRs. Recently, the bioactivation of TMP has been described as TMP N-acetyl cysteine (NAC) adducts were identified following human liver microsome (HLM) incubations and in the urine of children taking TMP, suggesting cytochrome P450 enzymes (P450s) catalyze TMP bioactivation. In this study, we identified the P450s involved in the formation of six TMP primary metabolites. Methods: A panel of characterized HLMs (n=16), c-DNA expressed P450s, and pooled HLMs in the presence and absence of selective P450 inhibitors were incubated with therapeutic concentrations of TMP. Reactive metabolites were trapped with NAC, and metabolite formation was quantified by UPLC/MS/MS. Correlation coefficients between the rates of metabolite formation and P450 marker reaction rates were determined using least-squares regression analysis and evaluated at α=0.05. Results: 1-NO-TMP, Cα-NAC-TMP and Cα-OH-TMP were formed by CYP3A4 and inhibited by ketoconazole (CYP3A inhibitor). 4'-demethylation was catalyzed by several P450s including CYP3A4, correlated with multiple CYPs, and inhibited primarily with ketoconazole suggesting CYP3A4 contributed to 4'-demethylation. 3-NO-TMP was formed by CYP1A and inhibited by α-naphthoflavone (CYP1A inhibitor). 3'-demethylation was catalyzed by multiple P450s including CYP2C9, correlated with CYP2C9 activity and inhibited by sulphafenazole (CYP2C9 inhibitor). Conclusion: These findings suggest that P450s were responsible for the primary metabolism of TMP with CYPs 2C9 and 3A4 being the most significant contributors to TMP primary metabolism. Factors modulating activity of these enzymes may affect the risk of IADRs.
    URI
    http://hdl.handle.net/1808/22543
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    • KU Med Center Dissertations and Theses [464]
    • Theses [3825]

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    785-864-8983
    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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