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Characterizing the mechanism of differential pharmacokinetic disposition of two structurally similar nucleoside reverse transcriptase inhibitors, zidovudine and didanosine
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Title
Characterizing the mechanism of differential pharmacokinetic disposition of two structurally similar nucleoside reverse transcriptase inhibitors, zidovudine and didanosine
Name
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Lee
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Sung-Hack
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Sung-Hack Lee
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(authority = RULIB)
author
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Sinko
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Patrick
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Advisory Committee
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Patrick J Sinko
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chair
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You
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Guofeng
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Advisory Committee
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Guofeng You
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internal member
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Michniak-Kohn
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Bozena
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Advisory Committee
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Bozena B Michniak-Kohn
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(authority = RULIB)
internal member
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Chong
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Saeho
Affiliation
Advisory Committee
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Saeho Chong
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outside member
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Rutgers University
Role
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(authority = RULIB)
degree grantor
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NamePart
Graduate School - New Brunswick
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(authority = RULIB)
school
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Text
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theses
OriginInfo
DateCreated
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2008
DateOther
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2008-05
Language
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English
PhysicalDescription
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electronic
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application/pdf
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text/xml
Extent
xii, 110 pages
Abstract
The differential contributions of efflux transporters and metabolizing enzymes to the disposition of zidovudine (azidothymidine, AZT) and didanosine (dideoxyinosine, ddI) were investigated using murine and human cells, mouse kidney slices, and mice. Cellular transport, transport in mouse kidney slices, brain uptake, and urinary excretion of AZT and ddI were investigated.
Fumitremorgin C (FTC), a breast cancer resistance protein (BCRP) specific inhibitor), increased AZT accumulation, but had little or no effect on ddI accumulation in either HEK-R482 or in J774. Involvement of BCRP was investigated by comparing results in Mock- and BCRP- transfected cells, and confirmed by repeating the studies after silencing BCRP using siRNA. MK-571, a MRP family inhibitor, blocked the efflux of AZT and ddI in murine and human cells. Silencing MRP3 and MRP4 attenuated the efflux of AZT while silencing MRP1 attenuated ddI efflux. The effect of blocking efflux transporters was found to be minor as compared to inhibition of metabolizing enzymes. The major form of AZT deposited inside murine cells was AZT-MP, while the major form found inside human cells was AZT-TP. MK-571 abolished the efflux of AZT-MP in both murine and human cells. However, the efflux of AZT, ddI and their metabolites was not affected by FTC. Application of MK-571 also decreased the efflux of GAZT and ddI in kidney slices. The urinary excretion of AZT and ddI with MK-571 in mice was measured. MK-571 did not cause any significant changes in the urinary excretion of AZT, ddI, or their metabolites between the MK-571 untreated and treated groups.
Collectively, the results of these studies indicate that AZT and ddI are substrates of BCRP and MRPs, however since their effects are limited in in situ and in vivo situation they appear to be relatively minor players in the overall disposition of these drugs.
Fumitremorgin C (FTC), a breast cancer resistance protein (BCRP) specific inhibitor), increased AZT accumulation, but had little or no effect on ddI accumulation in either HEK-R482 or in J774. Involvement of BCRP was investigated by comparing results in Mock- and BCRP- transfected cells, and confirmed by repeating the studies after silencing BCRP using siRNA. MK-571, a MRP family inhibitor, blocked the efflux of AZT and ddI in murine and human cells. Silencing MRP3 and MRP4 attenuated the efflux of AZT while silencing MRP1 attenuated ddI efflux. The effect of blocking efflux transporters was found to be minor as compared to inhibition of metabolizing enzymes. The major form of AZT deposited inside murine cells was AZT-MP, while the major form found inside human cells was AZT-TP. MK-571 abolished the efflux of AZT-MP in both murine and human cells. However, the efflux of AZT, ddI and their metabolites was not affected by FTC. Application of MK-571 also decreased the efflux of GAZT and ddI in kidney slices. The urinary excretion of AZT and ddI with MK-571 in mice was measured. MK-571 did not cause any significant changes in the urinary excretion of AZT, ddI, or their metabolites between the MK-571 untreated and treated groups.
Collectively, the results of these studies indicate that AZT and ddI are substrates of BCRP and MRPs, however since their effects are limited in in situ and in vivo situation they appear to be relatively minor players in the overall disposition of these drugs.
Note
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Ph.D.
Note
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Includes bibliographical references (p. 98-107).
Subject
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Topic
Pharmaceutical Science
Subject
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Topic
Pharmacokinetics
Subject
(ID = SUBJ3);
(authority = ETD-LCSH)
Topic
Reverse transcriptase
Subject
(ID = SUBJ4);
(authority = ETD-LCSH)
Topic
Nucleosides--Derivatives
Subject
(ID = SUBJ5);
(authority = ETD-LCSH)
Topic
AZT (Drug)
Subject
(ID = SUBJ6);
(authority = ETD-LCSH)
Topic
Antiviral agents
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Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17344
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ETD_923
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NjNbRU
Identifier
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doi:10.7282/T3GB24DP
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ETD doctoral
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The author owns the copyright to this work.
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Copyright protected
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Open
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Sung-Hack Lee
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Rutgers University. Graduate School - New Brunswick
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Non-exclusive ETD license
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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