{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:55:14Z","timestamp":1786978514820,"version":"build-2736575974"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P\u2010glycoprotein (P\u2010gp) and is therefore recommended for use in clinical drug\u2013drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P\u2010gp, it is susceptible to DDIs involving these proteins. Physiologically\u2010based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug\u2013drug(\u2013gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P\u2010gp perpetrators as well as CYP2D6 and P\u2010gp victims. The quinidine parent\u2010metabolite model including 3\u2010hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1\u2013600\u2009mg). The model covers efflux transport via P\u2010gp and metabolic transformation to either 3\u2010hydroxyquinidine or unspecified metabolites via CYP3A4. The 3\u2010hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two\u2010fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two\u2010fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is.<\/jats:p>","DOI":"10.1002\/psp4.12981","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T06:32:05Z","timestamp":1683786725000},"page":"1143-1156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Physiologically\u2010based pharmacokinetic modeling of quinidine to establish a\n                    <scp>CYP3A4<\/scp>\n                    , P\u2010gp, and\n                    <scp>CYP2D6 drug\u2013drug\u2013gene<\/scp>\n                    interaction network"],"prefix":"10.1002","volume":"12","author":[{"given":"Denise","family":"Feick","sequence":"first","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-2511","authenticated-orcid":false,"given":"Simeon","family":"R\u00fcdesheim","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"},{"name":"Dr. Margarete Fischer\u2010Bosch\u2010Institute of Clinical Pharmacology  Stuttgart Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima Zahra","family":"Marok","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Selzer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena Leonie Hanae","family":"Loer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacy Saarland University  Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donato","family":"Teutonico","sequence":"additional","affiliation":[{"name":"Translational Medicine &amp; Early Development Sanofi\u2010Aventis R&amp;D  Chilly\u2010Mazarin France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Frechen","sequence":"additional","affiliation":[{"name":"Bayer AG, Pharmaceuticals, Research &amp; Development Systems Pharmacology &amp; Medicine  Leverkusen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike","family":"van der Lee","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy &amp; Toxicology Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk Jan A. 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