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Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention
Author(s) -
Nicol Melanie R.,
Fedoriw Yuri,
Mathews Michelle,
Prince Heather M. A.,
Patterson Kristine B.,
Geller Elizabeth,
Mollan Katie,
Mathews Stephanie,
Kroetz Deanna L,
Kashuba Angela D. M.
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.248
Subject(s) - multidrug resistance associated protein 2 , maraviroc , organic anion transporter 1 , transporter , immunohistochemistry , biology , drug , medicine , pharmacology , immunology , atp binding cassette transporter , human immunodeficiency virus (hiv) , biochemistry , gene
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 3 efflux ( ABCB1 /MDR1, ABCC2 /MRP2, ABCC4 /MRP4) and 3 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). Hundred percent 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 ARV selection to target these tissues.