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dc.contributor.authorTaneva, Ekaterina S.
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 78-09(E), Section: B.;Advisors: Betsy C. Herold.
dc.description.abstractThe nucleotide reverse transcriptase inhibitor tenofovir (TFV), its prodrugs, TFV disoproxil fumarate (TDF) and TFV alafenamide (TAF), and the non-nucleoside reverse transcriptase inhibitor dapivirine (DPV) are in development for topical preexposure prophylaxis against HIV. TFV-based drugs also have potential to prevent HSV infection. Their antiviral activity requires cellular uptake and metabolism, but the drug transport mechanisms into human cells within the female genital tract are unknown. Furthermore, clinical trials with TFV and DPV showed variable efficacy. We hypothesized that differences in vaginal pH and microbiota may modulate drug pharmacokinetics (PK) and pharmacodynamics (PD).;Exposure of vaginal or T cells to TDF and TAF resulted in 40-fold higher intracellular levels of the active metabolite TFV-diphosphate than TFV. Permeability studies demonstrated that TDF and TAF entered cells passively, but their accumulation followed nonlinear kinetics, and unlabeled drugs competed with radiolabeled drugs, indicating saturation of carboxylesterases or cathepsin A, involved in TDF and TAF hydrolysis, respectively. In contrast, TFV uptake was inefficient, reflecting absence of organic anion transporters 1 and 3, and was mediated by non-saturable endocytic pathway(s). TFV uptake was reduced as pH increased from 5.0 to 7.5, but pH had no impact on TAF, TDF or DPV uptake. Lactobacillus crispatus have anionic transporters and kinases that were able to actively take up and metabolize TFV to TFV-DP. Additionally, supernatants from several bacteria modulated TFV endocytosis in T cells. Gardnerella vaginalis supernatants inhibited whereas Atopobium vaginae supernatants enhanced TFV uptake. Fractionation and mass spectroscopy identified the inhibitory molecule released by Gardnerella as adenine. None of the bacteria altered the PK of TDF or TAF. Similar effects on TFV PK were observed when TFV was incubated with vaginal swab eluants. There was also a significant reduction in DPV but not TDF or TAF availability. These findings indicate that DPV and TFV PK may be modified by vaginal pH and/or microbiota and may contribute to variable protection. Such effects would be overcome by sustained high drug levels. We demonstrated, for the first time, a role of the vaginal microbiome in drug PK, and uncovered a potential commensal interaction between Gardnerella and Atopobium .
dc.publisherProQuest Dissertations & Theses
dc.titleImpact of the Vaginal Microbiome on Antiretroviral Drug Pharmacokinetics and Pharmacodynamics

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