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dc.contributor.advisorFurge, Laura Lowe, 1971-
dc.contributor.authorGlass, Sarah M.
dc.descriptionvii, 57 p.en_US
dc.description.abstractHuman cytochrome P450 enzymes (CYPs) have a major role in the metabolism of drugs along with other endogenous and exogenous chemicals. Human CYP2D6 is responsible for approximately 12% of CYP-mediated drug metabolism. Metabolic phenotype can be affected by multiple factors including genetic polymorphism and interactions with inhibitors. With over 100 different allelic variants of CYP2D6 with metabolic profiles ranging from poor to ultra-rapid and a theoretically unlimited number of possible CYP2D6 substrates, there is a high possibility for altered drug responses and drug-drug interactions. Four CYP2D6 allelic variants, three with series of distal mutations (*34, *17-2, *17-3), one ultra-metabolizer (*53), along with one active site mutant (T309A) were expressed and purified in E. coli to further characterize their interactions with substrates and inhibitors. The effect of inactivation on 2D6 metabolism of the substrates dextromethorphan and bufuralol was investigated with SCH 66712. CYP2D6 variants showed altered susceptibility to inactivation; both T309A and *53 were not inactivated by SCH 66712 unlike 2D6*1. Limitations of in vitro inactivation assays for the prediction of in vivo effects were examined with paroxetine and rolapitant. Contrary to other literature, this study found paroxetine to not be a mechanism-based inactivator. This could explain the lack of adverse effects observed in vivo. On the other hand, rolapitant produces more effects in vivo than can be explained by completed in vitro assays that do not show a strong inhibitory potential. Combining knowledge about polymorphisms and inhibitors can reduce the occurrence of adverse drug events and has implications in personalized medicine and drug development.en_US
dc.publisherKalamazoo Collegeen_US
dc.relation.ispartofKalamazoo College Chemistry Senior Individualized Projects Collection
dc.rightsU.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder. All rights reserved.
dc.titleAltering CYP2D6 Phenotype : Comparison of CYP2D6 Polymorphisms and Evaluation of CYP2D6 Inhibition by SCH 66712, Paroxetine, and Rolapitanten_US
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  • Chemistry Senior Individualized Projects [860]
    This collection includes Senior Individualized Projects (SIP's) completed in the Chemistry Department. Abstracts are generally available to the public, but PDF files are available only to current Kalamazoo College students, faculty, and staff.

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