{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:01:43Z","timestamp":1788825703963,"version":"build-2803163510"},"reference-count":47,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"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":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>P\u2010glycoprotein (P\u2010gp) is an efflux transporter that plays an important role in the pharmacokinetics of its substrate, and P\u2010gp activities can be altered by induction and inhibition effects of rifampicin. This study aimed to establish a physiologically based pharmacokinetic (PBPK) model of rifampicin to predict the P\u2010gp\u2010mediated drug\u2013drug interactions (DDIs) and assess the DDI impact in the intestine, liver, and kidney. The induction and inhibition parameters of rifampicin for P\u2010gp were estimated using two of seven DDI cases of rifampicin and digoxin and incorporated into our previously constructed PBPK model of rifampicin. The constructed rifampicin model was verified using the remaining five DDI cases with digoxin and five DDI cases with other P\u2010gp substrates (talinolol and quinidine). Based on the established PBPK model, following repeated dosing of 600\u2009mg rifampicin, the deduced net effect was an approximately threefold induction in P\u2010gp activities in the intestine, liver, and kidney. Furthermore, in all 12 cases the predicted area under the plasma concentration\u2013time curve ratios of the P\u2010gp substrates were within the predefined acceptance criteria with various dosing regimens. Intestinal effects of P\u2010gp\u2013mediated DDIs had their greatest impact on the pharmacokinetics of digoxin and talinolol, with a minimal impact on the liver and kidney. For quinidine, predicted intestinal P\u2010gp\/cytochrome P450 3A\u2013mediated DDIs were slightly underestimated because of the complexity of nonlinearity and transporter\u2010enzyme interplay. These findings demonstrate that our rifampicin model can be applicable to quantitatively predict the net impact of P\u2010gp induction and\/or inhibition on diverse P\u2010gp substrates and investigate the magnitude of DDIs in each tissue.<\/jats:p>","DOI":"10.1002\/psp4.12807","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T03:49:46Z","timestamp":1652672986000},"page":"919-933","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Robust physiologically based pharmacokinetic model of rifampicin for predicting <scp>drug\u2013drug<\/scp> interactions via P\u2010glycoprotein induction and inhibition in the intestine, liver, and kidney"],"prefix":"10.1002","volume":"11","author":[{"given":"Ryuta","family":"Asaumi","sequence":"first","affiliation":[{"name":"Pharmacokinetic Research Laboratories Ono Pharmaceutical Co., Ltd.  Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken\u2010ichi","family":"Nunoya","sequence":"additional","affiliation":[{"name":"Pharmacokinetic Research Laboratories Ono Pharmaceutical Co., Ltd.  Ibaraki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Yamaura","sequence":"additional","affiliation":[{"name":"Pharmacokinetic Research Laboratories Ono Pharmaceutical Co., Ltd.  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