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In Vivo Modulation of Cervicovaginal Drug Transporters and Tissue Distribution by Film-Released Tenofovir and Darunavir for Topical Prevention of HIV‑1
journal contribution
posted on 2020-02-20, 14:34 authored by Karolin Hijazi, Francesco Iannelli, Anna Maria Cuppone, Delphine Desjardins, Anna Caldwell, Nathalie Dereuddre-Bosquet, Carlo Scala, Kieron A. Smith, Indrani Mukhopadya, Bruce Frank, Garry Gwozdz, Francesco Santoro, Roger Le Grand, Gianni Pozzi, Charles KellyClinical
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 nonhuman
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 h 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 preclinical 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.