{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:30:13Z","timestamp":1785781813158,"version":"3.56.0"},"reference-count":37,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T00:00:00Z","timestamp":1724025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF19OC0058275"],"award-info":[{"award-number":["NNF19OC0058275"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R307\u20102018\u20102980"],"award-info":[{"award-number":["R307\u20102018\u20102980"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004196","name":"Odense Universitetshospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>We aimed to assess if dicloxacillin\/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P\u2010glycoprotein (P\u2010gp) during 10 and 28\u2009days of treatment. To study the impact of dicloxacillin\/flucloxacillin on intestinal and hepatic expression of P\u2010gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin\/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10\u00a0days of 0.67 (95% confidence interval [CI]: 0.42\u20131.1) and geometric mean ratio 28\u2009days of 0.72 (95% CI: 0.39\u20131.4), suggesting reduced oral absorption via increased P\u2010gp expression. In vitro, dicloxacillin raised P\u2010gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke\/systemic embolism (dicloxacillin <jats:italic>vs<\/jats:italic>. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72\u20131.2; flucloxacillin <jats:italic>vs<\/jats:italic>. amoxicillin HR: 0.89, 95% CI: 0.51\u20131.5).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Dicloxacillin increases expression of intestinal P\u2010gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin\/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug\u2013drug interaction between dicloxacillin\/flucloxacillin and DOACs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16190","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T00:49:22Z","timestamp":1724114962000},"page":"3252-3262","source":"Crossref","is-referenced-by-count":4,"title":["Dicloxacillin is an inducer of intestinal P\u2010glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke\/systemic embolism in direct oral anticoagulant users"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5519-9091","authenticated-orcid":false,"given":"Ditte B.","family":"Iversen","sequence":"first","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-0909","authenticated-orcid":false,"given":"Ann\u2010Cathrine Dalg\u00e5rd","family":"Dunvald","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9003-3823","authenticated-orcid":false,"given":"Martin Thomsen","family":"Ernst","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0482-5563","authenticated-orcid":false,"given":"Shahab","family":"Abtahi","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7452-0477","authenticated-orcid":false,"given":"Patrick","family":"Souverein","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5604-813X","authenticated-orcid":false,"given":"Olaf","family":"Klungel","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University  the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn Br\u00f8de","family":"Jeppesen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-405X","authenticated-orcid":false,"given":"Flemming","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8444-7835","authenticated-orcid":false,"given":"Kim","family":"Br\u00f8sen","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health University of Southern Denmark  Odense 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