{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:24:15Z","timestamp":1790807055972,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Gates Foundation","doi-asserted-by":"publisher","award":["INV-040478"],"award-info":[{"award-number":["INV-040478"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"award":["INV-040478"],"award-info":[{"award-number":["INV-040478"]}],"id":[{"id":"https:\/\/ror.org\/0456r8d26","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000200","name":"United States Agency for International Development","doi-asserted-by":"publisher","award":["7200AA22CA00002"],"award-info":[{"award-number":["7200AA22CA00002"]}],"id":[{"id":"10.13039\/100000200","id-type":"DOI","asserted-by":"publisher"}]},{"award":["7200AA22CA00002"],"award-info":[{"award-number":["7200AA22CA00002"]}],"id":[{"id":"https:\/\/ror.org\/01n6e6j62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Given the potential for achieving high concentrations at the target site while limiting systemic exposure, delivering drugs directly to the female reproductive tract (FRT) is emerging as a promising strategy for enhancing women\u2019s reproductive health. However, quantitative data describing matrix-specific solubility, matrix-specific binding, and permeability across FRT tissues remain limited, constraining development of physiologically based pharmacokinetic (PBPK) models for intravaginal and intrauterine therapies. Methods: Our work was conducted to help fill this critical gap, evaluating four model drugs with diverse physicochemical and transporter profiles, dapivirine (DPV), levonorgestrel (LNG), MK-2048, and 4\u2032-ethynyl-2-fluoro-2\u2032-deoxyadenosine (EFdA; also known as islatravir or MK-8591) in in vitro and ex vivo human models. Plasma solubility, matrix-specific binding in plasma, cervicovaginal fluid, and FRT tissues, and bidirectional permeability across FRT tissues were quantified. Results: Our results demonstrated that the plasma solubility varied markedly across compounds, following lipophilicity trends, with DPV (34.14 \u00b1 1.04 \u00b5g\/mL) and EFdA (1808.02 \u00b1 67.36 \u00b5g\/mL) exhibiting the lowest and highest solubility, respectively. Hydrophobicity-dependent solubility enhancement by plasma proteins (~2\u00d7 to &gt;30\u00d7 higher comparing to aqueous solubility in the literature) was observed for all four model drugs. Apparent binding in plasma, cervicovaginal fluid, and FRT tissues was highly correlated with the model compounds\u2019 lipophilicity, with DPV having the most highly matrix-specific binding (97\u201399%) and EFdA having the least matrix-specific binding with the greatest variability (15\u201362%). Regional permeability differed significantly across FRT tissues: the human ectocervix, myometrium, endometrium, and fallopian tubes demonstrated distinct transport patterns consistent with epithelial architecture and the transporter-substrate status of the model compounds. Efflux transporter involvement was evident for MK-2048 and EFdA in Caco-2 models (efflux ratios 2.59 and 7.14, respectively), but was less pronounced in the 3D vaginal model and ex vivo tissues. Across all datasets, permeability and binding were strongly influenced by drug lipophilicity and ionization characteristics. Conclusions: Collectively, these findings demonstrate the interplay among solubility, matrix-specific binding, and tissue permeability in governing local drug distribution within the FRT. The experimentally derived parameters provide quantitative inputs for FRT PBPK model development, and are expected to inform design of safe and effective localized therapies for women\u2019s reproductive health.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070903","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:25:46Z","timestamp":1784726746000},"page":"903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Determining Critical Physiological and Drug Specific Parameters for Enhancing a Physiologically Based Pharmacokinetics Model for the Female Reproductive Tract"],"prefix":"10.3390","volume":"18","author":[{"given":"An","family":"Le","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1373-2222","authenticated-orcid":false,"given":"Riyazuddin","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5653-2554","authenticated-orcid":false,"given":"Junmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2017-3915","authenticated-orcid":false,"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1180-2530","authenticated-orcid":false,"given":"Guru R.","family":"Valicherla","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip W.","family":"Graebing","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-2252","authenticated-orcid":false,"given":"Robert","family":"Bies","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1602-0172","authenticated-orcid":false,"given":"Lisa C.","family":"Rohan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Magee-Womens Research Institute, Pittsburgh, PA 15213, USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113955","DOI":"10.1016\/j.addr.2021.113955","article-title":"Drug delivery strategies for management of women\u2019s health issues in the upper genital tract","volume":"177","author":"Patel","year":"2021","journal-title":"Adv. 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