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Tablet formulations (MTbLF) containing 300\u00a0mg of bLF progressed through three phases: Pre-Dissolution, Dissolution, and Washout, over a 30-h time course. Tablets dissolved slowly, replenishing intact 80\u00a0kDa bLF in vaginal fluid (VF) as proteolysis occurred. bLF was initially cleaved approximately in half between its N- and C-lobes, then degraded into sub-fragments and small peptides. The extent of proteolysis was less than 10\u201320% across multiple subjects. Concentrations of both intact 80\u00a0kDa bLF and smaller fragments decreased in VF with a similar time course suggesting washout not proteolysis was the main clearance mechanism. Concentrations of intact and\/or nicked 80\u00a0kDa bLF peaked between 4 and 8\u00a0h after administration and remained above 5\u00a0mg\/mL for approximately 24\u00a0h. Experiments with protease inhibitors in ex vivo VF digests suggested an aspartyl protease was at least partially responsible for bLF cleavage. However, digestion with commercial pepsin or in vivo in the human stomach, demonstrated distinctly different patterns of fragments compared to vaginal proteolysis. Furthermore, the 3.1\u00a0kDa antimicrobial peptide lactoferricin B was not detected in VF. This suggests pepsin-like aspartyl proteases are not responsible for vaginal proteolysis of bLF.<\/jats:p>","DOI":"10.1007\/s10534-022-00481-7","type":"journal-article","created":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T02:03:03Z","timestamp":1672279383000},"page":"531-547","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Proteolysis of vaginally administered bovine lactoferrin: clearance, inter-subject variability, and implications for clinical dosing"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5552-7190","authenticated-orcid":false,"given":"Thomas P.","family":"Hopp","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maura-Ann H.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaudyna","family":"Spiewak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zafeiria","family":"Athanasiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard S.","family":"Blackmore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary A.","family":"Gelbfish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"481_CR1","doi-asserted-by":"publisher","first-page":"63","DOI":"10.3109\/10408418609108735","volume":"13","author":"F Archibald","year":"1986","unstructured":"Archibald F (1986) Manganese: its acquisition by and function in the lactic acid bacteria. 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