dc.contributor.advisor | Mitra, Ashim K., 1954- | eng |
dc.contributor.author | Wang, Zhiying | eng |
dc.date.issued | 2015-05-22 | eng |
dc.date.submitted | 2013 Summer | eng |
dc.description | Title from PDF of title page, viewed on June 5, 2015 | eng |
dc.description | Dissertation advisor:Ashim K. Mitra | eng |
dc.description | Vita | eng |
dc.description | Includes bibliographic references (pages 173-194) | eng |
dc.description | Thesis (Ph.D.)--School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2013 | eng |
dc.description.abstract | Saquinavir (SQV) is the first antiretroviral protease inhibitor approved by Food and
Drug Administration in the United States for the treatment of HIV infection due to its
potent anti-HIV activity. However, some unfavorable properties including low aqueous
solubility, low intestinal absorption and fast biotransformation lead to its poor oral
bioavailability and limited therapeutic efficacy. The objective of this dissertation project
is to investigate whether stereoisomerized peptide prodrugs targeting influx transporter
system could improve intestinal absorption and oral bioavailability of SQV.
Four stereoisomeric dipeptide prodrugs of SQV including L-valine-L-valine-SQV
(LLS), L-valine-D-valine-SQV (LDS), D-valine-L-valine-SQV (DLS) and D-valine-Dvaline-
SQV (DDS) and two amino acid prodrugs including L-valine-SQV (LS) and Dvaline-
SQV (DS) were synthesized and investigated using in vitro cell culture models.
All dipeptide prodrugs exhibit improved aqueous solubility, lowered cytotoxicity, and
reduced P-gp/MRP2-mediated efflux activities regardless of stereochemistry in
promoieties. SQV attached with L-isomers shows higher affinity for peptide transporters
but lower stability and higher toxicity, whereas conjugation with D-isomers can enhance
stability and reduce toxicity, but not be recognized by peptide transporters. Subsequently,
results of metabolism studies performed in rat liver microsomes indicate that elimination
half life of SQV was prolonged dramatically by 7- to 40-fold due to prodrug modification
with the rank order of DDS > DLS > LDS > LLS > DS > LS > SQV. In comparison with
D-configuration, L-configuration favors the interaction between prodrugs and rat hepatic
CYP3A enzymes, resulting in a relatively rapid clearance by CYP3A. Stereoselectivity is
also observed in protein binding of prodrugs in rat plasma. Lower protein binding was
obtained by LS, LLS and LDS but higher by DS, DDS and DLS as compared with SQV.
Pharmacokinetics studies performed in rats provide further evidences that oral
bioavailability of SQV is drastically enhanced by conjugation with dipeptide L-valine-Dvaline.
In conclusion, stereoisomeric dipeptide prodrug modification targeting specific
influx transporters could be a successful strategy to improve bioavailability of poorly
absorbed drug SQV.
Additionally, influence of exogenous human efflux transporters (P-gp, MRP2 and
BCRP) on functional activities of endogenous peptide transporters (PepT) was also
delineated in MDR-transfected MDCK cell lines in this project. Results demonstrate that
overexpression of MDR genes reduces PepT function probably due to the phenomenon of
transporter-compensation resulting in down-regulation of endogenous genes. It may
provide some mechanistic insight into possible reasons for underestimation in drug
screening using these cell models. | eng |
dc.description.tableofcontents | Introduction -- Literature review -- Influence of efflux pumps on functional activities of peptide transporters in MDR-transfected MDCK cell lines -- Synthesis of stereoisomeric amino acid and dipeptide prodrugs of saquinavir -- Physicochemical properties and in vivo evaluation -- In vivo hydrolysis and enzymatic metabolism studies -- Evaluation of in vitro/in vivo bioavailability -- Summary and recommendations -- Appendix | eng |
dc.format.extent | xiv, 195 pages | eng |
dc.identifier.uri | https://hdl.handle.net/10355/45583 | eng |
dc.subject.lcsh | Antiretroviral agents -- Research | eng |
dc.subject.lcsh | Protease inhibitors | eng |
dc.subject.lcsh | Prodrugs | eng |
dc.subject.lcsh | Drug delivery systems | eng |
dc.subject.other | Dissertation -- University of Missouri--Kansas City -- Pharmacy | eng |
dc.subject.other | Dissertation -- University of Missouri--Kansas City -- Chemistry | eng |
dc.title | Transporter-Targeted Prodrug Delivery to Improve Oral
Bioavailability of Saquinavir | eng |
dc.type | Thesis | eng |
thesis.degree.discipline | Pharmaceutical Sciences (UMKC) | eng |
thesis.degree.discipline | Chemistry (UMKC) | |
thesis.degree.grantor | University of Missouri--Kansas City | eng |
thesis.degree.level | Doctoral | eng |
thesis.degree.name | Ph.D. | eng |