title: 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 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.
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Nicol
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fedoriw
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Mathews
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.|Center for AIDS Research, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Heather M A
authors.initials: HM
authors.lastname: Prince
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Geller
authors.affiliation: Center for AIDS Research, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Mollan
authors.affiliation: UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mathews
authors.affiliation: UCSF School of Pharmacy, University of California, San Francisco, NC, USA.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.|UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.|Center for AIDS Research, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D002584:Cervix Uteri / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008593:Menopause / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger / Q000378:metabolism; D012007:Rectum / Q000378:metabolism*; D014621:Vagina / Q000378:metabolism*
chemical_list: C000715087:ABCC2 protein, human; D019380:Anti-HIV Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger
keywords: HIV; antiretrovirals; mucosal; pharmacokinetics; prevention; transporters