{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:35:26Z","timestamp":1790962526950,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/X01603X\/1"],"award-info":[{"award-number":["BB\/X01603X\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"Abstract<\/jats:title>\n \n Understanding how pharmaceuticals cross the placenta is central to balancing effective maternal therapy with fetal safety. Computational and physiologically based pharmacokinetic models are powerful tools for predicting fetal drug exposure, but their accuracy depends on identifying the rate\u2010limiting determinants of placental transfer. These include placental anatomy, the routes available for paracellular diffusion, and the cellular localisation and membrane polarisation of drug transporters. The placenta both limits and mediates fetal exposure: it clears pharmaceuticals from the fetal circulation yet provides the principal route by which drugs reach the fetus. Transfer depends on a drug's physicochemical properties, especially molecular size and lipid solubility, and the presence of specific transport mechanisms. Net fetal exposure reflects the combined effects of diffusion and transporter\u2010mediated fluxes, plasma protein affinity, with a smaller contribution from placental metabolism. At the anatomical level recent advances in our understanding of placental ultrastructure have provided new routes allowing fetal exposure via diffusion. At the molecular level, defining transporter expression and polarisation is challenging and the literature is often inconsistent, reflecting methodological limitations. Single\u2010cell and single\u2010nucleus transcriptomics provide valuable insights into cell\u2010specific gene expression, although not necessarily protein localisation. Spatial mass spectrometry offers complementary information on protein abundance and polarity but remains limited by resolution. Effective models require a strong foundation in physiology and anatomy. A key limitation to modelling placental drug transfer is clearly determining the cellular localisation and membrane polarisation of drug transporters, and addressing this question is key to developing more effective predictive models.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>","DOI":"10.1113\/jp289604","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T01:19:56Z","timestamp":1776647996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Physiological and anatomical determinants of placental drug transfer"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4044-9104","authenticated-orcid":false,"given":"Rohan M.","family":"Lewis","sequence":"first","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Institute for Life Sciences University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandita","family":"Umapathy","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7978-4327","authenticated-orcid":false,"given":"Jane K.","family":"Cleal","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Southampton Southampton UK"},{"name":"Institute for Life Sciences University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram G.","family":"Sengers","sequence":"additional","affiliation":[{"name":"Institute for Life Sciences University of Southampton Southampton UK"},{"name":"Faculty of Engineering and Physical Sciences University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"issue":"10","key":"e_1_2_2_2_1","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.medj.2023.07.005","article-title":"Two distinct molecular faces of preeclampsia revealed by single\u2010cell transcriptomics","volume":"4","author":"Admati I.","year":"2023","journal-title":"Med"},{"key":"e_1_2_2_3_1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.bcp.2018.09.012","article-title":"Role of the efflux transporters BCRP and MRP1 in human placental bio\u2010disposition of pravastatin","volume":"156","author":"Afrouzian M.","year":"2018","journal-title":"Biochemical Pharmacology"},{"issue":"2","key":"e_1_2_2_4_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/toxsci\/kfs160","article-title":"Synchronized activity of organic cation transporter 3 (Oct3\/Slc22a3) and multidrug and toxin extrusion 1 (Mate1\/Slc47a1) transporter in transplacental passage of MPP+ in rat","volume":"128","author":"Ahmadimoghaddam D.","year":"2012","journal-title":"Toxicological Sciences"},{"issue":"3","key":"e_1_2_2_5_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1095\/biolreprod.112.105064","article-title":"Organic cation transporter 3 (OCT3\/SLC22A3) and multidrug and toxin extrusion 1 (MATE1\/SLC47A1) transporter in the placenta and fetal tissues: Expression profile and fetus protective role at different stages of gestation","volume":"88","author":"Ahmadimoghaddam D.","year":"2013","journal-title":"Biology of Reproduction"},{"key":"e_1_2_2_6_1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.71094","article-title":"Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit","volume":"11","author":"Ashley B.","year":"2022","journal-title":"eLife"},{"issue":"3","key":"e_1_2_2_7_1","doi-asserted-by":"crossref","first-page":"R677","DOI":"10.1152\/ajpregu.2000.278.3.R677","article-title":"Denudations as paracellular routes for alphafetoprotein and creatinine across the human syncytiotrophoblast","volume":"278","author":"Brownbill P.","year":"2000","journal-title":"American Journal of Physiology Regulatory, Integrative and Comparative Physiology"},{"issue":"3","key":"e_1_2_2_8_1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.reprotox.2006.01.007","article-title":"P\u2010glycoprotein in the placenta: Expression, localization, regulation and function","volume":"22","author":"Ceckova\u2010Novotna M.","year":"2006","journal-title":"Reproductive Toxicology"},{"issue":"4","key":"e_1_2_2_9_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1113\/jphysiol.2010.198549","article-title":"Facilitated transporters mediate net efflux of amino acids to the fetus across the basal membrane of the placental syncytiotrophoblast","volume":"589","author":"Cleal J. K.","year":"2011","journal-title":"The Journal of Physiology"},{"issue":"3","key":"e_1_2_2_10_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0006-2952(01)00890-5","article-title":"UDP\u2010glucuronosyltransferase activity, expression and cellular localization in human placenta at term","volume":"63","author":"Collier A. C.","year":"2002","journal-title":"Biochemical Pharmacology"},{"issue":"8","key":"e_1_2_2_11_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1124\/dmd.32.8.813","article-title":"Human placental glucuronidation and transport of 3\u2032azido\u20103\u2032\u2010deoxythymidine and uridine diphosphate glucuronic acid","volume":"32","author":"Collier A. C.","year":"2004","journal-title":"Drug Metabolism and Disposition: The Biological Fate of Chemicals"},{"issue":"2","key":"e_1_2_2_12_1","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/FTD.0b013e3181d0bd68","article-title":"Maternal buprenorphine dose, placenta buprenorphine, and metabolite concentrations and neonatal outcomes","volume":"32","author":"Concheiro M.","year":"2010","journal-title":"Therapeutic Drug Monitoring"},{"key":"e_1_2_2_13_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.placenta.2021.04.014","article-title":"Endocytosis in the placenta: An undervalued mediator of placental transfer","volume":"113","author":"Cooke L. D. F.","year":"2021","journal-title":"Placenta"},{"issue":"2","key":"e_1_2_2_14_1","doi-asserted-by":"crossref","first-page":"E352","DOI":"10.1152\/ajpendo.2000.278.2.E352","article-title":"Measurement of interstitial albumin in human skeletal muscle and adipose tissue by open\u2010flow microperfusion","volume":"278","author":"Ellmerer M.","year":"2000","journal-title":"American Journal of Physiology Endocrinology and Metabolism"},{"issue":"1","key":"e_1_2_2_15_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1124\/dmd.104.001560","article-title":"Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta","volume":"33","author":"Grube M.","year":"2005","journal-title":"Drug Metabolism and Disposition: The Biological Fate of Chemicals"},{"issue":"1","key":"e_1_2_2_16_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s12951-020-00676-5","article-title":"Plasma proteins facilitates placental transfer of polystyrene particles","volume":"18","author":"Gruber M. M.","year":"2020","journal-title":"Journal of Nanobiotechnology"},{"key":"e_1_2_2_17_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.placenta.2020.10.032","article-title":"Pericytes on placental capillaries in terminal villi preferentially cover endothelial junctions in regions furthest away from the trophoblast","volume":"104","author":"Harris S. E.","year":"2021","journal-title":"Placenta"},{"issue":"1","key":"e_1_2_2_18_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-15790-7","article-title":"Functional characterization of dopamine and norepinephrine transport across the apical and basal plasma membranes of the human placental syncytiotrophoblast","volume":"12","author":"Horackova H.","year":"2022","journal-title":"Scientific Reports"},{"key":"e_1_2_2_19_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0074-7696(06)60002-8","article-title":"Molecular mechanism of phase I and phase II drug\u2010metabolizing enzymes: Implications for detoxification","volume":"260","author":"Iyanagi T.","year":"2007","journal-title":"International Review of Cytology"},{"issue":"3","key":"e_1_2_2_20_1","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/j.1476-5381.2009.00430.x","article-title":"Impact of OATP transporters on pharmacokinetics","volume":"158","author":"Kalliokoski A.","year":"2009","journal-title":"British Journal of Pharmacology"},{"issue":"2","key":"e_1_2_2_21_1","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3390\/life12020166","article-title":"Fetal membranes contribute to drug transport across the feto\u2010maternal interface utilizing the breast cancer resistance protein (BCRP)","volume":"12","author":"Kammala A.","year":"2022","journal-title":"Life"},{"issue":"2","key":"e_1_2_2_22_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.mam.2012.10.010","article-title":"The SLC22 family with transporters of organic cations, anions and zwitterions","volume":"34","author":"Koepsell H.","year":"2013","journal-title":"Molecular Aspects of Medicine"},{"key":"e_1_2_2_23_1","first-page":"1","article-title":"Spatial proteomics towards cellular resolution","volume":"25","author":"Kwon Y.","year":"2024","journal-title":"Expert Review of Proteomics"},{"issue":"12","key":"e_1_2_2_24_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2022.105453","article-title":"3D visualization of trans\u2010syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast","volume":"25","author":"Lewis R. M.","year":"2022","journal-title":"Iscience"},{"issue":"20","key":"e_1_2_2_25_1","doi-asserted-by":"crossref","first-page":"4549","DOI":"10.1113\/JP270743","article-title":"Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast","volume":"593","author":"Lofthouse E. M.","year":"2015","journal-title":"The Journal of Physiology"},{"issue":"9","key":"e_1_2_2_26_1","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1016\/j.xphs.2023.05.008","article-title":"Computational modelling of paracellular diffusion and OCT3 mediated transport of metformin in the perfused human placenta","volume":"112","author":"Lofthouse E. M.","year":"2023","journal-title":"Journal of Pharmaceutical Sciences"},{"key":"e_1_2_2_27_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejps.2020.105436","article-title":"Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity","volume":"152","author":"Lofthouse E. M.","year":"2020","journal-title":"European Journal of Pharmaceutical Sciences"},{"issue":"1","key":"e_1_2_2_28_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.bbrc.2018.10.074","article-title":"Estrone sulphate uptake by the microvillous membrane of placental syncytiotrophoblast is coupled to glutamate efflux","volume":"506","author":"Lofthouse E. M.","year":"2018","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"1","key":"e_1_2_2_29_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1208\/s12248-014-9668-6","article-title":"Role of the breast cancer resistance protein (BCRP\/ABCG2) in drug transport\u2013An update","volume":"17","author":"Mao Q.","year":"2015","journal-title":"The AAPS Journal"},{"issue":"2","key":"e_1_2_2_30_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.molmed.2022.11.001","article-title":"ABC transporters: Human disease and pharmacotherapeutic potential","volume":"29","author":"Moore J. M.","year":"2023","journal-title":"Trends in Molecular Medicine"},{"issue":"1","key":"e_1_2_2_31_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.placenta.2005.12.010","article-title":"Metabolism of synthetic steroids by the human placenta","volume":"28","author":"Murphy V. E.","year":"2007","journal-title":"Placenta"},{"issue":"3","key":"e_1_2_2_32_1","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.bcp.2004.04.011","article-title":"Methadone metabolism by human placenta","volume":"68","author":"Nanovskaya T. N.","year":"2004","journal-title":"Biochemical Pharmacology"},{"issue":"1","key":"e_1_2_2_33_1","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/joa.13082","article-title":"Human placental villi contain stromal macrovesicles associated with networks of stellate cells","volume":"236","author":"Palaiologou E.","year":"2020","journal-title":"Journal of Anatomy"},{"key":"e_1_2_2_34_1","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jtbi.2014.10.042","article-title":"Computational modelling of amino acid exchange and facilitated transport in placental membrane vesicles","volume":"365","author":"Panitchob N.","year":"2015","journal-title":"Journal of Theoretical Biology"},{"issue":"7","key":"e_1_2_2_35_1","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/j.bbamem.2016.03.028","article-title":"Computational modelling of placental amino acid transfer as an integrated system","volume":"1858","author":"Panitchob N.","year":"2016","journal-title":"Biochimica et Biophysica Acta"},{"key":"e_1_2_2_36_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fphar.2012.00126","article-title":"Drug interactions at the human placenta: What is the evidence?","volume":"3","author":"Rubinchik\u2010Stern M.","year":"2012","journal-title":"Frontiers in Pharmacology"},{"issue":"14","key":"e_1_2_2_37_1","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.1113\/jphysiol.2009.172403","article-title":"Understanding placental nutrient transfer\u2013why bother? New biomarkers of fetal growth","volume":"587","author":"Sibley C. P.","year":"2009","journal-title":"The Journal of Physiology"},{"key":"e_1_2_2_38_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.placenta.2017.10.010","article-title":"DNA methylation of amino acid transporter genes in the human placenta","volume":"60","author":"Simner C.","year":"2017","journal-title":"Placenta"},{"issue":"2","key":"e_1_2_2_39_1","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1210\/jc.2017-02140","article-title":"Transfer and metabolism of cortisol by the isolated perfused human placenta","volume":"103","author":"Stirrat L. I.","year":"2018","journal-title":"The Journal of Clinical Endocrinology and Metabolism"},{"key":"e_1_2_2_40_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.placenta.2021.11.002","article-title":"Folding of the syncytiotrophoblast basal plasma membrane increases the surface area available for exchange in human placenta","volume":"117","author":"Tashev S. A.","year":"2022","journal-title":"Placenta"},{"issue":"6220","key":"e_1_2_2_41_1","doi-asserted-by":"crossref","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue\u2010based map of the human proteome","volume":"347","author":"Uhl\u00e9n M.","year":"2015","journal-title":"Science"},{"issue":"2","key":"e_1_2_2_42_1","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41588-023-01647-w","article-title":"Single\u2010nucleus multi\u2010omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy","volume":"56","author":"Wang M.","year":"2024","journal-title":"Nature Genetics"},{"key":"e_1_2_2_43_1","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.3389\/fimmu.2017.01294","article-title":"Factors affecting the FcRn\u2010mediated transplacental transfer of antibodies and implications for vaccination in pregnancy","volume":"8","author":"Wilcox C. R.","year":"2017","journal-title":"Frontiers in Immunology"},{"key":"e_1_2_2_44_1","doi-asserted-by":"crossref","DOI":"10.1155\/2008\/927574","article-title":"The metabolism and transplacental transfer of oseltamivir in the ex vivo human model","volume":"2008","author":"Worley K. C.","year":"2008","journal-title":"Infectious Diseases in Obstetrics and Gynecology"},{"issue":"8","key":"e_1_2_2_45_1","doi-asserted-by":"crossref","first-page":"e00199","DOI":"10.1128\/AAC.00199-19","article-title":"Multiple drug transporters contribute to the placental transfer of emtricitabine","volume":"63","author":"Zeng Q.","year":"2019","journal-title":"Antimicrobial Agents and Chemotherapy"},{"issue":"12","key":"e_1_2_2_46_1","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1016\/j.bcp.2009.08.003","article-title":"Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide","volume":"78","author":"Zharikova O. L.","year":"2009","journal-title":"Biochemical Pharmacology"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP289604","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP289604","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP289604","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T01:20:01Z","timestamp":1776648001000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP289604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,19]]},"references-count":45,"alternative-id":["10.1113\/JP289604"],"URL":"https:\/\/doi.org\/10.1113\/jp289604","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,19]]},"assertion":[{"value":"2025-11-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"JP289604"}}