Zheng, Ruohui
(2022)
Active Efflux Transporters in Human Female Reproductive Tract: Interplay with Antiretrovirals and Strategies to Overcome Substrate Efflux.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
HIV still threatens the health of millions of people, with 1.5 million people being infected by HIV in 2021. Approximately half of the new infections occurred in women and according to CDC, 84% of them were due to heterosexual contact through receptive vaginal sex. Women living in low- and middle-income countries with high HIV prevalence and women facing potential sexual violence are at higher risk of HIV infection. Although a few drug products to prevent HIV transmission have been approved and shown to be effective, the occurrence of the COVID-19 pandemic has further highlighted the discrepancies in people’s access to healthcare services. To provide women with more available options for HIV prevention, effective products that are self-administrated, affordable, portable, and discreet need to be developed.
It is known that the biodistribution of a number of antiretroviral drugs is impacted by efflux transporters. The work presented here focused on elucidating the roles of efflux transporters in the disposition of antiretrovirals and developing strategies to overcome substrate efflux. Specifically, transporter interactions with two promising drug candidates for HIV prevention, dapivirine (DPV) and MK-2048, were evaluated using vesicular and cellular systems. The potential use of ex vivo human cervical models to study drug-transporter interactions was also evaluated. Furthermore, the effectiveness of efflux inhibitory synthetic block copolymers (Pluronics) in enhancing substrate penetration into human female reproductive tract (FRT) tissue and the feasibility of formulating such agents into a vaginal film dosage form were demonstrated.
Briefly, in this work, we found that: (1) DPV does not interact with transporters that are highly expressed in human FRT, while MK-2048 is a substrate of P-gp and BCRP; (2) The polarized human cervical explant retains barrier function limiting passive transport but has no active P-gp/BCRP, while freshly excised human cervix demonstrates active efflux of MK-2048; (3) Pluronic L61 and P84 improve MK-2048 penetration into freshly excised human cervix by inhibiting P-gp efflux; and (4) Pluronic P84 can be incorporated into vaginal films without introducing drastic changes in film characteristics.
Collectively, this project (1) explored the potential interactions between DPV and transporters highly expressed in human FRT, which provided important information for the regulatory filings; (2) explored the potential interactions between MK-2048 and transporters highly expressed in human FRT; (3) demonstrated the capability of freshly excised human cervix to be used for studying drug-transporter interactions, which was the first ex vivo model of human FRT used for this purpose; and (4) investigated the impact of efflux inhibitory Pluronics on MK-2048 tissue penetration and the feasibility of incorporating Pluronics into vaginal films, which provides a potential formulation strategy to overcome substrate efflux in human FRT.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
2 December 2022 |
| Date Type: |
Publication |
| Defense Date: |
5 August 2022 |
| Approval Date: |
2 December 2022 |
| Submission Date: |
29 November 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
201 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HIV prevention; female reproductive tract; drug transporter; vaginal drug delivery. |
| Date Deposited: |
02 Dec 2022 18:14 |
| Last Modified: |
02 Dec 2022 18:14 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43906 |
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