• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Applications of Bile Acid Transporters in Drug Delivery and Enterohepatic Circulation Assessment

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Vivian_umaryland_0373D_10517.pdf
    Size:
    3.042Mb
    Format:
    PDF
    Download
    Author
    Vivian, Diana
    Advisor
    Polli, James E.
    Date
    2014
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    The objective of this dissertation was to investigate the application of modified bile acids for the assessment of bile acid enterohepatic circulation and for prodrug development. Bile Acid Malabsorption (BAM) results in excess fecal bile acid levels and chronic, intermittent diarrhea. Although BAM may account for up to 30% of patients diagnosed as irritable bowel syndrome (IBS-D), current methods of diagnosis are limited, and BAM is thought to be underdiagnosed. To address this gap, two trifluorinated bile acids were developed for use in fluorine magnetic resonance imaging (MRI) of bile acid enterohepatic circulation. CA-lys-TFA was synthesized by conjugating trifluoroacetyl lysine to cholic acid. CA-lys-TFA was a potent inhibitor and substrate of both the apical sodium dependent bile acid transporter and the Na+/taurocholate cotransporting polypeptide. Stability results were favorable in most conditions tested, but in choloylglycine hydrolase (CGH), the compound showed deconjugation. A preliminary pharmacokinetic analysis showed that accumulation of CA-lys-TFA in the gallbladder was maximal within 4 to 7 h. In vivo mouse imaging after oral dosing showed reproducible, clear <super>19</super>F signal from the gallbladder. This represents the first report of in vivo imaging of an orally absorbed drug using <super>19</super>F MRI. To improve upon CA-lys-TFA, CA-sar-TFMA was synthesized as potentially more stable against deconjugation in the intestine. CA-sar-TFMA was a potent inhibitor and substrate of ASBT and NTCP. Contrary to CA-lys-TFA, CA-sar-TFMA showed no degradation when exposed to CGH, and was successfully imaged in the mouse gallbladder. Both CA-lys-TFA and CA-sar-TFMA showed significantly lower concentrations in the gallbladders of Asbt-deficient mice (Slc10A2-/-), which have impaired bile acid transport relative to their WT littermates. These findings suggest that fluorinated non-radioactive bile acid analogues have potential for use in MRI to measure in vivo bile acid transport and diagnose bile acid malabsorption and other conditions associated with impaired bile acid transport. Additionally, two bile acid prodrugs of floxuridine were developed to target the liver through NTCP uptake. Finally, a model of substrate translocation in the presence of an inhibitor was derived to determine the impact of microrate constants on K<sub>m</sub>, K<sub>i</sub>, and V<sub>max</sub>.
    Description
    University of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2014
    Keyword
    bile acids
    bile acid malabsorption
    transporter
    Bile Acids and Salts
    Fluorine-19 Magnetic Resonance Imaging
    Prodrugs
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/4084
    Collections
    Theses and Dissertations School of Pharmacy
    Theses and Dissertations All Schools

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.