Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention

Abstract

Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected three efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and three uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). 100% of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (p<0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9 fold > colorectal; vaginal ABCC2 2.9 fold>colorectal; colorectal ABCC4 2.0 fold>cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate antiretroviral selection to target these tissues.

Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis

“…Moreover, OAT substrates, such as estrone-3-sulfate, did not inhibit TFV uptake (not shown). The absence of OAT1 and OAT3 expression is consistent with recent studies, in which these transporters were not detected in the majority of cervical or vaginal biopsy specimens but were expressed, albeit at low levels, in 100% of the colorectal biopsy specimens (37,38). Consistent with this, we also have not shown OAT1 expression in vaginal biopsy specimens.…”

“…Consistent with this, we also have not shown OAT1 expression in vaginal biopsy specimens. It has been speculated that low-level OAT1 expression in colonic tissue combined with high colorectal luminal drug concentrations contributed to the 100-fold higher TFV levels in colorectal than vaginal tissue after oral dosing (38,39). The notion that OATs mediate TFV uptake comes primarily from in vitro studies using transfected cells or Xenopus oocytes overexpressing the transporters (15,23,29).…”

Challenges and potential barriers to the uptake of antiretroviral-based prevention in Asia and the Pacific region

“…39 Other factors such as pharmacology of antiretrovirals in the female versus male genital tract and differences in genital tract inflammation among study populations are also being investigated. 40,41 A Phase III study of daily oral TDF among IDUs in Thailand demonstrated an overall 49% effectiveness in the modified intention-to-treat analysis. 42,43 Efficacy was also highly dependent on adherence.…”

Short Communication: Cheminformatics Analysis to Identify Predictors of Antiviral Drug Penetration into the Female Genital Tract

“…Moreover, a study by Nicol et al using real-time PCR (qPCR) provided quantitative evidence of a high expression of MRP4 (120-310% of liver expression) in the epithelial and submucosal cells of vaginal and cervical tissue. 13 The findings from these studies thus provide a biologically plausible foundation on which to build a predictive model for FGT penetration using both structural and biological characteristics of drugs.…”

“…Considering recent evaluations of transporter and metabolizing enzyme expression in the FGT showing several possible contributors to penetration, 12,13 we hypothesized that the development of a predictive model could benefit from the incorporation of drugs' transporter profiles and other biological parameters as additional molecular descriptors. Zhou et al 12 examined the expression of 19 transporters in the FGT using reverse transcriptase polymerase chain reaction (RT-PCR) and found that several uptake (OCT2, ENT1, OATP-D) and efflux (MDR1, BCRP, and MRPs 1, 4, 5, and 7) transporters were qualitatively expressed at levels equal to or greater than the liver.…”