{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:43:02Z","timestamp":1787244182489,"version":"build-2736575974"},"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sangi Co., Ltd."},{"name":"Sangi Co., Ltd."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    We earlier reported that coating poorly water-soluble drugs with nano-hydroxyapatite (nano-HAP) improves bioavailability after oral administration. In the present study, we coated BCS Class IV drug acetazolamide (AZ) with nano-HAP (AZ\/HAP formulation), and investigated its bioavailability and nano-HAP\u2019s role in promoting it.\n                    <jats:italic>We tested AZ bioavailability after a single oral dose of the AZ\/HAP formulation in rats<\/jats:italic>\n                    ,\n                    <jats:italic>followed by a series of in vitro<\/jats:italic>\n                    ,\n                    <jats:italic>ex vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    testing. The binding state of AZ and nano-HAP was analyzed by gel filtration chromatography. AZ permeability was studied using a Caco-2 cell monolayer assay kit, to test for tight junction penetration, then using an Ussing chamber mounted with intestinal epithelium, both with and without Peyer\u2019s patch tissue, to examine the role of intracellular transport. Fluorescence-labeled nano-HAP particles were administered orally in rats to investigate their localization in the intestinal tract. The area under the blood concentration time-curve in rats was about 4 times higher in the AZ\/HAP formulation group than in the untreated AZ group. Gel filtration analysis showed AZ and nano-HAP were not bound. The Caco-2 study showed equivalent AZ permeability for both groups, but without significant change in transepithelial electrical resistance (TEER), indicating that tight junctions were not penetrated. In the Ussing chamber study, no significant difference in AZ permeability between the two groups was observed for epithelium containing Peyer\u2019s patch tissue, but for epithelium without Peyer\u2019s patch tissue, at high concentration, significantly higher permeability in the AZ\/HAP formulation group was observed. Fluorescent labeling showed nano-HAP particles were present in both intestinal villi and Peyer\u2019s patch tissue 30 min after oral administration. Our results suggest that nano-HAP\u2019s enhancement of drug permeability from the small intestine occurs not via tight junctions, but intracellularly, via the intestinal villi. Further study to elucidate the mechanism of this permeability enhancement is required.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0268067","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T13:59:47Z","timestamp":1652968787000},"page":"e0268067","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Nano-hydroxyapatite improves intestinal absorption of acetazolamide (BCS Class IV drug)\u2013but how?"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5891-0670","authenticated-orcid":true,"given":"Kenichi","family":"Kaneko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Miyasaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roslyn","family":"Hayman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"issue":"10","key":"pone.0268067.ref001","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.7150\/ijbs.24612","article-title":"Review of drug repositioning approaches and resources","volume":"14","author":"H Xue","year":"2018","journal-title":"Int J Biol Sci"},{"issue":"2","key":"pone.0268067.ref002","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cbi.2006.12.006","article-title":"Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach.","volume":"171","author":"IM Kapetanovic","year":"2008","journal-title":"Chem Biol Interact"},{"issue":"3","key":"pone.0268067.ref003","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.drudis.2018.11.018","article-title":"Computational modeling for formulation design.","volume":"24","author":"CH Mehta","year":"2019","journal-title":"Drug Discov Today"},{"issue":"3","key":"pone.0268067.ref004","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd3078","article-title":"How to improve R&D productivity: the pharmaceutical industry\u2019s grand challenge","volume":"9","author":"SM Paul","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0268067.ref005","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jconrel.2017.01.014","article-title":"BCS class IV drugs: Highly notorious candidates for formulation development","volume":"248","author":"R Ghadi","year":"2017","journal-title":"J Control Release"},{"issue":"6","key":"pone.0268067.ref006","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1021\/mp0600182","article-title":"A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain and Japan.","volume":"3","author":"T Takagi","year":"2006","journal-title":"Mol Pharm"},{"key":"pone.0268067.ref007","first-page":"107","volume-title":"Oral liquid-based formulations. 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