{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T21:14:54Z","timestamp":1768598094379,"version":"3.49.0"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007807","name":"Japan Science Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Apixaban, a factor Xa inhibitor, is a direct oral anticoagulant with a well\u2010balanced elimination; it is eliminated evenly via feces, urine (with no active secretion), and as metabolites after oral administration. The common understanding is that biliary secretion and enterohepatic circulation (EHC) of apixaban are limited in humans, and that fecal excretion may be attributable to intestinal secretion. However, a decrease in apixaban blood concentration with activated charcoal coadministration in humans suggests possible involvement of EHC. This study aimed to evaluate the contribution of biliary excretion, EHC, and intestinal secretion to apixaban pharmacokinetics (PK) using a physiologically\u2010based pharmacokinetic (PBPK) model. A top\u2010down analysis was performed using blood concentration and mass balance data from healthy volunteers. Model parameters were optimized using the Cluster\u2010Gauss Newton method (CGNM), followed by the bootstrap method. The model accurately described observed data and indicated moderate to high biliary secretion relative to metabolic clearance. Simulated biliary secretion into the duodenum well predicted the biliary secretion data in humans (&lt;\u20091% of dose at 8\u2009h post\u2010dose). Virtual knockout of EHC resulted in a shortened half\u2010life from 8.7 to 2.9\u2009h, and 17% and 55% decrease in area under the concentration curve (AUC) and fecal excretion after intravenous dosing, respectively, confirming the significant contribution of biliary excretion and EHC. The model also accurately described apixaban PK with activated charcoal coadministration at 2 or 6\u2009h post\u2010dose. Although further experimental validation (e.g., sandwich\u2010cultured hepatocytes) would strengthen these findings, our study demonstrates that biliary secretion and EHC play a substantial role in apixaban elimination and disposition in humans.<\/jats:p>","DOI":"10.1002\/psp4.70163","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T06:40:52Z","timestamp":1764744052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterizing Apixaban Pharmacokinetics Through Physiologically\u2010Based Pharmacokinetic Modeling: Critical Role of Biliary Secretion and Enterohepatic Circulation in Humans"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7257-3196","authenticated-orcid":false,"given":"Toshiaki","family":"Tsuchitani","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy Keio University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Kou","sequence":"additional","affiliation":[{"name":"Innovation Base Josai International University (JIU)  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatoshi","family":"Tomi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Keio University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Innovation Base Josai International University (JIU)  Tokyo Japan"},{"name":"iHuman Institute ShanghaiTech University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.990"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04369.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.023143"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.029694"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01720"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.050575"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.04.043"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2.6.875"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100288"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40256-013-0055-y"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12807"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13154"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.70047"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.000023"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.04.044"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2024.101011"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11081-020-09571-2"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13055"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00775-z"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1446"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.009118"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.023465"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-05216-z"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.119.086918"},{"key":"e_1_2_9_26_1","first-page":"311","article-title":"The Use of Activated Charcoal to Treat Intoxications","volume":"116","author":"Zellner T.","year":"2019","journal-title":"Deutsches \u00c4rzteblatt International"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00879-x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2023.2287472"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.050260"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-017-0434-x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2020.01.002"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01051-9"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14743"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12977"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-018-2430-8"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12562"}],"container-title":["CPT: Pharmacometrics &amp; 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