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INTRACELLULAR DRUG-DRUG INTERACTION BETWEEN NUCLEOSIDE
ANALOGS LEADS TO EARLY VIROLOGIC FAILURE IN HIV PATIENTS
RECEIVING TRIPLE NUCLEOSIDE COMBINATIONS OF TENOFOVIR,
LAMIVUDINE AND ABACAVIR OR DIDANOSINE
by
Lucun Bi
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2008
Copyright 2008 Lucun Bi
Object Description
| Title | Intracellular drug-drug interaction between nucleoside analogs leads to early virologic failure in HIV patients receiving triple nucleoside combinations of tenofovir, lamivudine and abacavir or didanosine |
| Author | Bi, Lucun |
| Author email | lucunbi@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2007-11-29 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-03-15 |
| Advisor (committee chair) | Burckart, Gilbert J. |
| Advisor (committee member) |
Louie, Stan Shen, Wei-Chiang D'Argenio, David Wang, Clay C. C. |
| Abstract | High level of virologic failure was observed in HIV patients receiving combinations of tenofovir (TFV), lamivudine (3TC) combined with either abacavir (ABC) or didanosine (ddI). To investigate the pharmacologic mechanisms involve with the virologic failures, a comprehensive study was undertaken to evaluate the intracellular concentration of the active moiety (ddNTP) of these respective nucleoside analogs.; Triple nucleoside combinations were tested at physiological concentrations revealed reductions of 5 to 33% of the respective ddNTP. In vitro studies evaluating TFV and ABC in a concentration dependent manner showed a reduction of 40% and 30% in intracellular CBV-TP and TFV-DP. Similar findings were demonstrated with TFV and ddI, where 40% and 25% reduction in ddATP and TFV-DP, respectively, was detected. The level of dATP and dGTP, endogenous nucleotides, were increased by 2.4- and 2.7-fold, respectively, when cells were treated with 20 µM TFV, which can dilute the effect of ddNTP.; The expression of MRP2 and MRP4 were increased in cells serially passaged in either ABC or TFV, which correlated with cellular viability in the presence of high concentrations of nucleosides. Moreover, these cells had significantly lower level of ddNTP accumulation as compared to the wild type counterparts.; A clinical study was undertaken to evaluate whether the in vitro findings were also observed in humans. The combination of ABC and TDF resulted in a 2-fold increase in intracellular TFV-DP in patients receiving the combination of ABC and TFV as compared to TDF alone. Increases in TFV-DP may be attributed to higher plasma level of TFV, which was detected in the second phase of this study. A 4-fold increase in CBV-TP was detected three of nine patients, while the other six (6/9) had a 41% reduction. The degree of CBV-TP reduction is consistent with what is seen in vitro.; These findings suggest that cellular adaptive are critical in reducing intracellular levels of nucleoside analogs and their corresponding ddNTP, which may increase risk of virologic failures. The underlying pharmacological mechanisms may include but are not limited to, the competitive inhibition of anabolic enzymes, increase expression of efflux transporters and increase dATP and dGTP, where the resultant effect is reduced antiviral activity. |
| Keyword | nucleoside analog; NRTI; intracellular drug-drug interaction; efflux transporters; MRP2; MRP4; cellular adaptive response; ddNTP; TFV; ABC; ddI; endogenous nucleotide pools; PNP |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1051 |
| Contributing entity | University of Southern California |
| Rights | Bi, Lucun |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Bi-20080315 |
| Archival file | uscthesesreloadpub_Volume17/etd-Bi-20080315.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | INTRACELLULAR DRUG-DRUG INTERACTION BETWEEN NUCLEOSIDE ANALOGS LEADS TO EARLY VIROLOGIC FAILURE IN HIV PATIENTS RECEIVING TRIPLE NUCLEOSIDE COMBINATIONS OF TENOFOVIR, LAMIVUDINE AND ABACAVIR OR DIDANOSINE by Lucun Bi A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) May 2008 Copyright 2008 Lucun Bi |
