{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:57:23Z","timestamp":1791053843681,"version":"4.1.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":20,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K08 AI134262"],"award-info":[{"award-number":["K08 AI134262"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007249","name":"University of Minnesota","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007249","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007930","name":"Clinical & Translational Sciences","doi-asserted-by":"publisher","award":["1UM1TR004405-01A1"],"award-info":[{"award-number":["1UM1TR004405-01A1"]}],"id":[{"id":"10.13039\/100007930","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019303","name":"UMN","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019303","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Women's Health Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The female genital tract (FGT) is a unique compartment with physiologically distinct properties complicating the extrapolation of drug efficacy; critical gaps remain in understanding regional variability within the FGT itself. We performed an in-depth investigation across endo- and ectocervical tissues on the utility of the cervical explant model to evaluate pre-exposure prophylaxis (PrEP) efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using normal cervical tissues, we evaluated gene expression of relevant drug metabolizing enzymes and transporters (DMETs) via qRT-PCR and compared ecto- and endocervix. To determine differences in drug phosphorylation and to assess antiretroviral (ARV) efficacy, we incubated explants in tenofovir and emtricitabine then measured intracellular metabolites. Viral infectivity and dose\u2013response with ARVs was measured using viral RNA and p24 following HIV-1JR-CSF challenge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ABCC4 expression was 3-fold lower in ectocervical tissues compared with endocervical, whereas CYP3A5 was 2-fold higher. IL-6 was correlated with ABCB1 (r\u200a=\u200a0.52, P\u200a=\u200a0.01) and ABCG2 (r\u200a=\u200a0.56, P\u200a=0.005). Dose-normalized phosphorylation did not differ between endo- and ectocervix (P\u200a&amp;gt;\u200a0.5). Infectivity of explants was low (53%) but did not differ by compartment. Intracellular tenofovir diphosphate concentrations were associated with a decrease in ectocervical viral replication (r\u200a=0.39, P\u200a&amp;lt;\u200a0.05). There was a strong relationship between the proportion of explants infected and emtricitabine dose (P\u200a=0.02) but no relationship between intracellular emtricitabine triphosphate and protection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified differences in DMET expression and ARV metabolism between ecto- and endocervical tissues, as well as correlations between DMET and IL-6. Ectocervical explants demonstrated consistent viral infectivity and dose-dependent inhibition. The model is useful in determining tenofovir diphosphate targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkag103","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T06:12:01Z","timestamp":1774332721000},"source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological evaluation of an\n                    <i>ex vivo<\/i>\n                    cervicovaginal HIV prevention model"],"prefix":"10.1093","volume":"81","author":[{"given":"Lindsey B","family":"Collins","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy , University of Minnesota Twin Cities, Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy , University of Minnesota Twin Cities, Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5513-5509","authenticated-orcid":false,"given":"Melanie R","family":"Nicol","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy , University of Minnesota Twin Cities, Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"2026032402115668800_dkag103-B1","author":"Joint United Nations Programme on HIV\/AIDS"},{"key":"2026032402115668800_dkag103-B2","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1002\/jcph.1270","article-title":"Pharmacology of antiretrovirals in the female genital tract for HIV prevention","volume":"58","author":"Nicol","year":"2018","journal-title":"J Clin Pharmacol"},{"key":"2026032402115668800_dkag103-B3","doi-asserted-by":"publisher","first-page":"e9310","DOI":"10.1371\/journal.pone.0009310","article-title":"In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide","volume":"5","author":"Rohan","year":"2010","journal-title":"PLoS One"},{"key":"2026032402115668800_dkag103-B4","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1093\/jac\/dks173","article-title":"Reformulated tenofovir gel for use as a dual compartment microbicide","volume":"67","author":"Dezzutti","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"2026032402115668800_dkag103-B5","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1093\/jac\/dks097","article-title":"Intravaginal ring delivery of tenofovir disoproxil fumarate for prevention of HIV and herpes simplex virus infection","volume":"67","author":"Mesquita","year":"2012","journal-title":"J Antimicrob Chemother"},{"key":"2026032402115668800_dkag103-B6","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1097\/QAI.0000000000000472","article-title":"Models for predicting effective HIV chemoprevention in women","volume":"68","author":"Nicol","year":"2015","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2026032402115668800_dkag103-B7","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1128\/AAC.01156-08","article-title":"Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor","volume":"53","author":"Fletcher","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"2026032402115668800_dkag103-B8","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1089\/aid.2022.0057","article-title":"Translational models to predict target concentrations for pre-exposure prophylaxis in women","volume":"38","author":"Lantz","year":"2022","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2026032402115668800_dkag103-B9","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1093\/jac\/dkq447","article-title":"Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection","volume":"66","author":"Anderson","year":"2011","journal-title":"J Antimicrob Chemother"},{"key":"2026032402115668800_dkag103-B10","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.bcp.2013.08.013","article-title":"Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues","volume":"86","author":"To","year":"2013","journal-title":"Biochem Pharmacol"},{"key":"2026032402115668800_dkag103-B11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1097\/QAD.0000000000001678","article-title":"The role of menopause in tenofovir diphosphate and emtricitabine triphosphate concentrations in cervical tissue","volume":"32","author":"Nicol","year":"2018","journal-title":"AIDS"},{"key":"2026032402115668800_dkag103-B12","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1128\/AAC.01129-06","article-title":"Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture","volume":"51","author":"Cummins","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"2026032402115668800_dkag103-B13","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1124\/mol.106.028233","article-title":"Functional involvement of multidrug resistance-associated protein 4 (MRP4\/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir","volume":"71","author":"Imaoka","year":"2007","journal-title":"Mol Pharmacol"},{"key":"2026032402115668800_dkag103-B14","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1097\/QAI.0b013e31815e7478","article-title":"Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV-infected patients","volume":"47","author":"Kiser","year":"2008","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2026032402115668800_dkag103-B15","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1089\/aid.2013.0281","article-title":"Expression and localization of p-glycoprotein, multidrug resistance protein 4, and breast cancer resistance protein in the female lower genital tract of human and pigtailed macaque","volume":"30","author":"Zhou","year":"2014","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2026032402115668800_dkag103-B16","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1002\/jcph.248","article-title":"Expression of six drug transporters in vaginal, cervical, and colorectal tissues: implications for drug disposition in HIV prevention","volume":"54","author":"Nicol","year":"2014","journal-title":"J Clin Pharmacol"},{"key":"2026032402115668800_dkag103-B17","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1089\/aid.2016.0073","article-title":"Analytical advances in the ex vivo challenge efficacy assay","volume":"33","author":"Richardson-Harman","year":"2017","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2026032402115668800_dkag103-B18","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/mi.2011.34","article-title":"Enhanced HIV-1 replication in ex vivo ectocervical tissues from post-menopausal women correlates with increased inflammatory responses","volume":"4","author":"Rollenhagen","year":"2011","journal-title":"Mucosal Immunol"},{"key":"2026032402115668800_dkag103-B19","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1111\/aji.12198","article-title":"Distribution of immune cells in the human cervix and implications for HIV transmission","volume":"71","author":"Trifonova","year":"2014","journal-title":"Am J Reprod Immunol"},{"key":"2026032402115668800_dkag103-B20","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1089\/aid.2017.0107","article-title":"Heterogeneity of HIV-1 replication in ectocervical and vaginal tissue ex vivo","volume":"34","author":"Dezzutti","year":"2018","journal-title":"AIDS Res Hum Retroviruses"},{"key":"2026032402115668800_dkag103-B21","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1095\/biolreprod.105.043133","article-title":"Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone","volume":"73","author":"Pudney","year":"2005","journal-title":"Biol Reprod"},{"key":"2026032402115668800_dkag103-B22","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/nature07831","article-title":"Glycerol monolaurate prevents mucosal SIV transmission","volume":"458","author":"Li","year":"2009","journal-title":"Nature"},{"key":"2026032402115668800_dkag103-B23","doi-asserted-by":"publisher","first-page":"3180","DOI":"10.1093\/jac\/dkac300","article-title":"A post-mortem analysis of tenofovir, lamivudine, efavirenz and fluconazole penetration in female genital tissues","volume":"77","author":"Wang","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2026032402115668800_dkag103-B24","doi-asserted-by":"publisher","first-page":"112re4","DOI":"10.1126\/scitranslmed.3003174","article-title":"Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission","volume":"3","author":"Patterson","year":"2011","journal-title":"Sci Transl Med"},{"key":"2026032402115668800_dkag103-B25","doi-asserted-by":"publisher","first-page":"100893","DOI":"10.1016\/j.eclinm.2021.100893","article-title":"Safety and pharmacokinetics of a tenofovir alafenamide fumarate-emtricitabine based oral antiretroviral regimen for prevention of HIV acquisition in women: a randomized controlled trial","volume":"36","author":"Thurman","year":"2021","journal-title":"EClinicalMedicine"},{"key":"2026032402115668800_dkag103-B26","doi-asserted-by":"publisher","first-page":"12633","DOI":"10.1016\/S0021-9258(18)99923-0","article-title":"Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2',3'-dideoxynucleoside analogs in resting and activated human cells","volume":"269","author":"Gao","year":"1994","journal-title":"J Biol Chem"},{"key":"2026032402115668800_dkag103-B27","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.1128\/AAC.39.11.2555","article-title":"Comparative analysis of anti-human immunodeficiency virus type 1 activities of dideoxynucleoside analogs in resting and activated peripheral blood mononuclear cells","volume":"39","author":"Shirasaka","year":"1995","journal-title":"Antimicrob Agents Chemother"},{"key":"2026032402115668800_dkag103-B28","doi-asserted-by":"publisher","first-page":"104409","DOI":"10.1016\/j.isci.2022.104409","article-title":"The ex vivo pharmacology of HIV-1 antiretrovirals differs between macaques and humans","volume":"25","author":"Herrera","year":"2022","journal-title":"iScience"},{"key":"2026032402115668800_dkag103-B29","doi-asserted-by":"publisher","first-page":"3768","DOI":"10.1007\/s11095-015-1738-7","article-title":"Pharmacodynamic activity of dapivirine and maraviroc single entity and combination topical gels for HIV-1 prevention","volume":"32","author":"Dezzutti","year":"2015","journal-title":"Pharm Res"},{"key":"2026032402115668800_dkag103-B30","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1097\/QAD.0000000000002974","article-title":"The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate","volume":"35","author":"Herrera","year":"2021","journal-title":"AIDS"},{"key":"2026032402115668800_dkag103-B31","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1093\/infdis\/jiw077","article-title":"A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine","volume":"214","author":"Cottrell","year":"2016","journal-title":"J Infect Dis"}],"container-title":["Journal of Antimicrobial Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/4\/dkag103\/67493036\/dkag103.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jac\/article-pdf\/81\/4\/dkag103\/67493036\/dkag103.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T06:12:03Z","timestamp":1774332723000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jac\/article\/doi\/10.1093\/jac\/dkag103\/8539051"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,4]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,3,4]]}},"URL":"https:\/\/doi.org\/10.1093\/jac\/dkag103","relation":{},"ISSN":["0305-7453","1460-2091"],"issn-type":[{"value":"0305-7453","type":"print"},{"value":"1460-2091","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,3,4]]},"article-number":"dkag103"}}