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.
- Multidrug resistance associated protein
- multidrug resistance associated protein
- PROTEASE INHIBITORS
- VAGINAL RINGS
- EFFLUX TRANSPORTERS
- REVERSE-TRANSCRIPTASE INHIBITORS
- DISOPROXIL FUMARATE
- INTRACELLULAR ACCUMULATION
ASJC Scopus subject areas
- Drug Discovery
- Molecular Medicine
- Pharmaceutical Science