{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T08:44:57Z","timestamp":1785746697872,"version":"3.56.0"},"reference-count":34,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Dicloxacillin is a penicillinase\u2010resistant beta\u2010lactam antibiotic and potent activator of the Pregnane X receptor (PXR), known to induce CYP2C9, CYP2C19, and CYP3A4 activity. Clinical data suggest it reduces anticoagulation in warfarin\u2010treated patients and increases the risk of thromboembolic events. This open\u2010label, sequential drug\u2013drug interaction study quantitatively evaluated the effect of dicloxacillin on the pharmacokinetics of warfarin and phenytoin, two prototype CYP2C9 substrates with narrow therapeutic indices, and possible impact of\n                    <jats:italic>CYP2C9<\/jats:italic>\n                    polymorphisms on the extent of this interaction. Twenty\u2010eight healthy non\u2010smoker subjects, 15 carriers of\n                    <jats:italic>CYP2C9*1\/*1,<\/jats:italic>\n                    and 13 carriers of a single\n                    <jats:italic>CYP2C9*2<\/jats:italic>\n                    or\n                    <jats:italic>CYP2C9*3<\/jats:italic>\n                    allele, received single doses of warfarin (20\u2009mg) and 1\u2009week later, phenytoin (300\u2009mg) before and during a 21\u2010day course of dicloxacillin 500\u2009mg four times daily. Plasma concentration of warfarin enantiomers and phenytoin and urine concentration of p\u2010HPPH were measured using validated HPLC methods. Warfarin pharmacodynamics was monitored via serial INR measurements for up to 120\u2009hours. Dicloxacillin increased oral clearance of (\n                    <jats:italic>S<\/jats:italic>\n                    )\u2010warfarin and (\n                    <jats:italic>R<\/jats:italic>\n                    )\u2010warfarin by 53.2% and 63.2%, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). The area under the INR\u2010time curve decreased by 15.5% (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Phenytoin oral clearance and p\u2010HPPH formation clearance increased by 42.4% and 40.5%, respectively (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). CYP2C9 induction was significantly greater in carriers of\n                    <jats:italic>CYP2C9*1\/*1<\/jats:italic>\n                    genotype and INR reduction was more pronounced among\n                    <jats:italic>VKORC1 AA<\/jats:italic>\n                    haplotype carriers. Dicloxacillin substantially induces the metabolism of warfarin and phenytoin. Whenever dicloxacillin is initiated, the dose of CYP2C9 substrates characterized by a narrow therapeutic window should be increased and drug levels and\/or pharmacodynamic response should be closely monitored.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70413","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:54:15Z","timestamp":1785743655000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Effect of Dicloxacillin Administration on Pharmacokinetics of Narrow Therapeutic Window Drugs: Phenytoin and Warfarin"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7064-0781","authenticated-orcid":false,"given":"Chanan","family":"Shaul","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Unit, Division of Medicine Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"},{"name":"Institute of Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7044-5625","authenticated-orcid":false,"given":"Waseem","family":"Mujahed","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Division of Medicine Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Idries","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Division of Medicine Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7241-4670","authenticated-orcid":false,"given":"Maor","family":"Wanounou","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Division of Medicine Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"},{"name":"Institute of Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-4171","authenticated-orcid":false,"given":"Meir","family":"Bialer","sequence":"additional","affiliation":[{"name":"Institute of Drug Research School of Pharmacy, Faculty of Medicine, Hebrew University  Jerusalem Israel"},{"name":"David R. Bloom Center for Pharmacy The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7959-2517","authenticated-orcid":false,"given":"Yoseph","family":"Caraco","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit, Division of Medicine Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm8010001"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.12.007"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1998.00721.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200342090-00003"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.12.3408-3413.2000"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0897190018772978"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/14017439950141443"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1662"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.15738"},{"key":"e_1_2_9_10_1","first-page":"804","article-title":"Effect of dicloxacillin sodium on the hypoprothrombinemic response to warfarin sodium","volume":"6","author":"Krstenansky P.M.","year":"1987","journal-title":"Clin. 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