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Review
. 2015 Dec 10:219:681-696.
doi: 10.1016/j.jconrel.2015.08.018. Epub 2015 Aug 13.

Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery

Minlu Hu  1 , Sravan Kumar Patel  1 , Tian Zhou  1 , Lisa C Rohan  2
Affiliations
Review

Drug transporters in tissues and cells relevant to sexual transmission of HIV: Implications for drug delivery

Minlu Hu et al. J Control Release. .

Abstract

Efflux and uptake transporters of drugs are key regulators of the pharmacokinetics of many antiretroviral drugs. A growing body of literature has revealed the expression and functionality of multiple transporters in female genital tract (FGT), colorectal tissue, and immune cells. Drug transporters could play a significant role in the efficacy of preventative strategies for HIV-1 acquisition. Pre-exposure prophylaxis (PrEP) is a promising strategy, which utilizes topically (vaginally or rectally), orally or other systemically administered antiretroviral drugs to prevent the sexual transmission of HIV to receptive partners. The drug concentration in the receptive mucosal tissues and target immune cells for HIV is critical for PrEP effectiveness. Hence, there is an emerging interest in utilizing transporter information to explain tissue disposition patterns of PrEP drugs, to interpret inter-individual variability in PrEP drug pharmacokinetics and effectiveness, and to improve tissue drug exposure through modulation of the cervicovaginal, colorectal, or immune cell transporters. In this review, the existing literature on transporter expression, functionality and regulation in the transmission-related tissues and cells is summarized. In addition, the relevance of transporter function for drug delivery and strategies that could exploit transporters for increased drug concentration at target locales is discussed. The overall goal is to facilitate an understanding of drug transporters for PrEP optimization.

Keywords: Colorectal tissue; Female genital tract (FGT); HIV prevention; Immune cells; Pre-exposure prophylaxis (PrEP); Transporters.

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Figures

Figure 1
Figure 1. Anatomy and transporter expression in the female genital tract
The FGT that are potential sites of sexual HIV transmission include uterus, endocervix, ectocervix, and vagina. A mucus layer covers the epithelia of all these tissue segments, serving as a physical barrier to vaginally administered drugs. Stratified, squamous epithelial layers line the vagina and ectocervix, and a single-layer of columnar epithelial cells lines the endocervix and uterus. The epithelial layers and stroma are separated by the collagen-rich laminar propria. The CD4+ T cells, dentritic cells and macrophages are HIV target cells, and they are distributed in epithelial layers, stroma, and draining lymph nodes. The invading HIV particles can infect these immune cells and establish local tissue infection, expansion, and progress to systemic dissemination. Blood vessels (veins, arteries) and lymphatic vessels mediate the distribution of drug between the tissues and systemic compartments (circulating blood and lymph). LCs, Langerhan’s cells, which are the dentritic cells residing in peripheral tissues. EC, epithelial cells. (The figure is based on Zhou et al. [62])
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