In vivo modulation of cervicovaginal drug transporters and tissue distribution by film-released tenofovir and darunavir for topical prevention of HIV-1

Karolin Hijazi* (Corresponding Author), Francesco Iannelli, Anna Maria Cuppone, Delphine Desjardins, Anna Caldwell, Nathalie Dereuddre-Bosquet, Carlo Scala, Kieron A Smith, Indrani Mukhopadhya, Bruce Frank, Garry Gwozdz, Francesco Santoro, Roger Le Grand, Gianni Pozzi, Charles G Kelly

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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Clinical trials have demonstrated partial protection against HIV-1 infection by vaginal microbicide formulations based on antiretroviral (ARV) drugs. Improved formulations that will maintain sustained drug concentrations at viral target sites in the cervicovaginal mucosa are needed. We have previously demonstrated that treatment of cervicovaginal cell lines with ARV drugs can alter gene expression of drug transporters, suggesting that the mucosal disposition of ARV drugs delivered vaginally can be modulated by drug transporters.
This study aimed to investigate in vivo modulation of drug transporter expression in a non-human primate model by tenofovir and darunavir released from film formulations.
Cervicovaginal tissues were collected from drug-naïve macaques and from macaques vaginally treated with film formulations of tenofovir or darunavir. Drug release in vaginal fluid as well as drug absorption in cervicovaginal tissues and lymph nodes were verified by mass spectrometry. The effects of exposure to drugs on the expression of transporters relevant to ARV drugs were evaluated by quantitative PCR.
We showed expression in cervicovaginal tissue of drug-naïve macaques of transporters important for distribution of ARV drugs, albeit at lower levels compared to human tissue for key transporters including P-glycoprotein. Concentrations of tenofovir and darunavir well above the EC50 values determined in vitro were detected in vaginal fluid and vaginal tissues of macaques treated with drug-dissolving films over 24 hours and were also comparable to those shown previously to modulate drug transporter expression. Accordingly, Multidrug Resistance associated Protein 2 (MRP2) in cervicovaginal tissue was upregulated by both tenofovir and darunavir. The two drugs also differentially induced and/or inhibited expression of key uptake transporters for reverse transcriptase inhibitors and protease inhibitors.
The lower expression of key transporters in macaques may result in increased retention of ARV drugs at the simian cervicovaginal mucosa compared to the human mucosa and has implications for translation of pre-clinical data. Modulation of drug transporter expression by tenofovir and darunavir points to the potential benefit of MRP2 inhibition to increase ARV drug penetration through the cervicovaginal epithelium.
Original languageEnglish
Pages (from-to)852-864
Number of pages13
JournalMolecular Pharmaceutics
Issue number3
Early online date4 Feb 2020
Publication statusPublished - 2 Mar 2020

Bibliographical note

We thank Gilead Science for provision of tenofovir and Janssen R&D Ireland for provision of darunavir. We thank members of the MOTIF consortium for useful discussions and exchange of ideas during the course of this study. We thank the technical staff of IDMIT, the animal care and veterinary staff at CEA, Fontenay-aux-Roses, France. Funding: this work was supported by the European Union's Seventh Programme for research, technological development and demonstration under grant agreement No 305316 as part of the MOTIF (Microbicides Formulation Through Innovative Formulation for Vaginal and Rectal Delivery) project. It has also the support of the “Investissements d’Avenir” French government program managed by the Agence Nationale de la Recherche under ANR-11-INBS-0008 funding for the Infectious Disease Models and Innovative Therapies (IDMIT, Fontenay-aux-Roses, France) infrastructure, and ANR-10-EQPX-02-01 funding for the FlowCyTech facility (IDMIT, Fontenay-aux-Roses, France).


  • Multidrug resistance associated protein
  • tenofovir
  • darunavir
  • microbicides
  • vagina
  • macaques
  • multidrug resistance associated protein


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