Zhou, Tian
(2014)
Expression, Regulation and Function of Drug Transporters in Tissues and Cells Relevant to HIV-1 Sexual Transmission.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Although some clinical trials have shown the promise of antiretroviral-based topical and oral pre-exposure prophylaxis (PrEP) products in the prevention of HIV-1 sexual transmission, other studies have achieved inconsistent results. Drug exposure in the cervicovaginal tissues, colorectal tissue, and immune cells positively correlates with PrEP effectiveness, and there is an urgent need to identify critical physiologic determinants of drug exposure in these relevant tissues and cells, to inform product optimization. Drug transporters are important regulators of antiretroviral pharmacokinetics. This dissertation aims to examine the expression, regulation, and function of drug transporters in human cervicovaginal and colorectal tissues, as well as in the animal models and cell lines utilized in PrEP product testing.
Multiple efflux and uptake transporters, including P-gp, BCRP, MRP4, 5, 7 and ENT1, were found to be positively expressed in the cervicovaginal and colorectal tissues of humans, macaques, rabbits, and mice. A smaller panel of transporters were positively detected in three epithelial cell lines (End1/E6E7, Ect1/E6E7, VK2/E6E7) derived from human endocervix, ectocervix, vagina, and a T cell line (PM1). Menstrual cycle, exogenous hormones, contraceptives, and proinflammatory cytokines were found to impact transporter expression in mice and/or cell lines. The protein expression of P-gp, BCRP, and MRP4 was demonstrated using immunohistochemical staining, in the cervicovaginal and colorectal tissues of humans, macaques and mice. The transporters were found to localize at multiple cell types along the cervicovaginal tract, and the protein abundance and localization of transporters were affected by menstrual cycle and hormone/contraceptive use in a mouse model. In a Depo-Provera synchronized mouse model, the co-administration of MRP4 inhibitor MK571 with TFV vaginal gel or intraperitoneal TFV solution significantly increased TFV concentration, in tissues and fluids relevant to HIV transmission. However, MK571 exerted differential effects on the distribution of vaginally administered TFV, when MK571 was given via different routes. Collectively, these studies have shown that antiretroviral drug-related transporters are positively expressed in tissues and cells relevant to HIV-1 sexual transmission, and their expression can be regulated by hormones and cytokines. Further, the studies have provided proof of concept on Mrp4 function in TFV exposure in cervicovaginal and colorectal tissues.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
24 October 2014 |
| Date Type: |
Publication |
| Defense Date: |
18 July 2014 |
| Approval Date: |
24 October 2014 |
| Submission Date: |
23 October 2014 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
207 |
| 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: |
Transporters, microbicides, PrEP, female genital tract, colorectal tissue, drug exposure |
| Date Deposited: |
24 Oct 2014 15:00 |
| Last Modified: |
24 Oct 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/23407 |
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