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

Hu, Minlu; Patel, Sravan Kumar; Zhou, Tian; Rohan, Lisa C.

doi:10.1016/j.jconrel.2015.08.018

Cited by 27 publications

(43 citation statements)

References 237 publications

(281 reference statements)

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“…Similar high RAL penetration was seen in our study in rectal and intestinal tissues. This higher and differential accumulation in various tissues compared to plasma akin to that seen in human studies may be attributable to several factors that include differential and selective expression and localization of drug transporters in distinct mucosal compartments (45,46). …”

Section: Discussionmentioning

confidence: 93%

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Veselinović

Yang²,

Sykes³

et al. 2016

Virology

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Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data.

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Section: Discussionmentioning

confidence: 93%

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Veselinović

Yang²,

Sykes³

et al. 2016

Virology

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“…We and others have reported that several efflux transporters, including P-gp, BCRP, and MRP4, were positively or even highly expressed in the cervicovaginal and colorectal tissues of human, macaque, rabbit, and mouse, as well as the cell lines derived from human cervicovaginal or colorectal tissues [24–30]. These animal models are used in PrEP microbicide testing.…”

Section: Introductionmentioning

confidence: 99%

Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing

Zhou

Pearlman

et al. 2016

Biochemical Pharmacology

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P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4) are three efflux transporters that play key roles in the pharmacokinetics of antiretroviral drugs used in the pre-exposure prophylaxis of HIV sexual transmission. In this study, we investigated the expression, regulation, and function of these transporters in cervicovaginal tissues of a mouse model. Expression and regulation were examined using real-time RT-PCR and immunohistochemical staining, in the mouse tissues harvested at estrus and diestrus stages under natural cycling or after hormone synchronization. The three transporters were expressed at moderate to high levels compared to the liver. Transporter proteins were localized in various cell types in different tissue segments. Estrous cycle and exogenous hormone treatment affected transporter mRNA and protein expression, in a tissue- and transporter-dependent manner. Depo-Provera-synchronized mice were dosed vaginally or intraperitoneally with 3H-TFV, with or without MK571 co-administration, to delineate the function of cervicovaginal Mrp4. Co-administration of MK571 significantly increased the concentration of vaginally-administered TFV in endocervix and vagina. MK571 increased the concentration of intraperitoneally-administered TFV in the cervicovaginal lavage and vagina by several fold. Overall, P-gp, Bcrp, and Mrp4 were positively expressed in mouse cervicovaginal tissues, and their expression can be regulated by the estrous cycle or by exogenous hormones. In this model, the Mrp4 transporter impacted TFV distribution in cervicovaginal tissues.

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“…Although highly variable, some reports suggest that tenofovir diphosphate (TFVdp) kinetics differs across cell types within cervical tissue. Louissaint et al estimated median (interquartile range) TFVdp halflives of 34 (21,40), 82 (43,89), and 60 (52,72) when measured by cervical tissue homogenate, total disaggregated cells from a cervical biopsy, and isolated cervical CD4 cells, respectively. 14 More research in this area is needed but is limited by the small number of cells in a typical biopsy and assay limitations for quantification.…”

Section: Heterosexual Transmission and Anatomy Of The Female Genital mentioning

confidence: 99%

Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

Nicol

Corbino

Cottrell

2018

The Journal of Clinical Pharma

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Preexposure prophylaxis (PrEP) is a powerful tool that, as part of a comprehensive prevention package, has potential to significantly impact the HIV epidemic. PrEP effectiveness is believed to be dependent on the exposure and efficacy of antiretrovirals at the site of HIV transmission. Clinical trial results as well as modeling and simulation indicate the threshold of adherence required for PrEP efficacy of emtricitabine/tenofovir disoproxil fumarate may differ between sites of HIV transmission with less forgiveness for missed doses in women exposed through genital tissue compared to people exposed through colorectal tissue. This suggests a role for local and host factors to influence mucosal pharmacology. Here we review the mucosal pharmacology of antiretrovirals in the female genital tract and explore potential determinants of PrEP efficacy. Host factors such as inflammation, coinfections, hormonal status, and the vaginal microbiome will be explored as well as the role of drug-metabolizing enzymes and transporters in regulating local drug exposure. The use of preclinical and early clinical models to predict clinical effectiveness is also discussed.

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

Cited by 27 publications

References 237 publications

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis

Expression, regulation, and function of drug transporters in cervicovaginal tissues of a mouse model used for microbicide testing

Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

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