{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T08:39:49Z","timestamp":1789893589865,"version":"4.0.1"},"reference-count":17,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015R1A5A1008958"],"award-info":[{"award-number":["2015R1A5A1008958"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Korea Small and Medium Business Administration","award":["the World Class 300 project R&D"],"award-info":[{"award-number":["the World Class 300 project R&D"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Concomitant use of rivaroxaban with non-dihydropyridine calcium channel blockers (non-DHPs) might lead to an increase of systemic rivaroxaban exposure and anticoagulant effects in relation to the inhibition of metabolic enzymes and\/or transporters by non-DHPs. This study was designed to evaluate the effects of verapamil and diltiazem on the pharmacokinetics and the prolongation of prothrombin time of rivaroxaban in rats. The data were analyzed using a pharmacokinetic\/pharmacodynamics (PK\/PD) modeling approach to quantify the influence of verapamil. Verapamil increased the systemic exposure of rivaroxaban by 2.8-fold (p &lt;0.001) which was probably due to the inhibition of efflux transportation rather than metabolism. Prothrombin time was also prolonged in a proportional manner; diltiazem did not show any significant effects, however. A transit PK model in the absorption process comprehensively describes the double-peaks of rivaroxaban plasma concentrations and the corresponding change of prothrombin time with a simple linear relationship. The slope of prothrombin time vs. rivaroxaban plasma concentration in rats was retrospectively found to be insensitive by about 5.4-fold compared to than in humans. More than a 67% dose reduction in rivaroxaban is suggested in terms of both a pharmacokinetic point of view, and the sensitivity differences on the prolongation of prothrombin time when used concomitantly with verapamil.<\/jats:p>","DOI":"10.3390\/pharmaceutics11030133","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T12:12:25Z","timestamp":1552997545000},"page":"133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Effects of Verapamil and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban"],"prefix":"10.3390","volume":"11","author":[{"given":"Minsoo","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heebin","family":"Son","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keumhan","family":"Noh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, ON M5S 3M2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-8805","authenticated-orcid":false,"given":"Eunyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6706-5445","authenticated-orcid":false,"given":"Beom Soo","family":"Shin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonku","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1538-7836.2005.01166.x","article-title":"In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor","volume":"3","author":"Perzborn","year":"2005","journal-title":"J. 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Pharmacokinet."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/3\/133\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:39:05Z","timestamp":1760186345000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/3\/133"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,19]]},"references-count":17,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["pharmaceutics11030133"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11030133","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,19]]}}}