{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:04:20Z","timestamp":1789700660562,"version":"4.0.1"},"reference-count":47,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Renal clearance (CL\n                    <jats:sub>\n                      <jats:italic>r<\/jats:italic>\n                    <\/jats:sub>\n                    ) is the net outcome of glomerular filtration, secretion, and reabsorption, which makes the quantitative requirements for net renal secretion difficult to infer from simple clearance models. Using a mechanistic kidney model (MechKiM), we simulated blood\u2010referenced CL\n                    <jats:sub>\n                      <jats:italic>r<\/jats:italic>\n                    <\/jats:sub>\n                    (CL\n                    <jats:sub>\n                      <jats:italic>r,b<\/jats:italic>\n                    <\/jats:sub>\n                    ) for 30,000 virtual drugs (neutral, monoanionic, and monocationic) under continuous infusion and across all eight combinations of three proximal\u2010tubule transporters (basal uptake, basal efflux, apical efflux). Net renal secretion (clearance ratio CR\u2009=\u2009CL\n                    <jats:sub>\n                      <jats:italic>r,b<\/jats:italic>\n                    <\/jats:sub>\n                    \/(\n                    <jats:italic>f<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>u,b<\/jats:italic>\n                    <\/jats:sub>\n                    \u2009\u00d7\u2009GFR)\u2009&gt;\u20091.5, where\n                    <jats:italic>f<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>u,b<\/jats:italic>\n                    <\/jats:sub>\n                    and GFR are the unbound fraction in blood and the glomerular filtration rate) occurred only when basal uptake transport was present; apical efflux alone produced proximal secretion that was offset by downstream reabsorption, yielding no net secretion. In the scenario where all three transporters were present within the MechKiM framework, five quantitative criteria distinguished secretion\u2010type drugs, including basal transporter\u2010mediated uptake (&gt;\u20094.2\u2009L\/h) and its fractional contribution to total basal uptake (&gt;\u200994% for non\u2010cationic compounds). Clinical CL\n                    <jats:sub>\n                      <jats:italic>r,p<\/jats:italic>\n                    <\/jats:sub>\n                    (plasma\u2010referenced CL\n                    <jats:sub>\n                      <jats:italic>r<\/jats:italic>\n                    <\/jats:sub>\n                    ) versus in\u00a0vitro uptake\u2010transporter data (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009217) and published MechKiM\u2010PBPK models (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200919, typically assigning &gt;\u200999% of basal uptake to transporters) were consistent with these findings. A sufficient contribution of basal uptake transporters in the proximal tubule is essential for observing net renal secretion. This study provides quantitative, in\u00a0vitro\u2010translatable criteria to anticipate renal secretion and transporter\u2010mediated drug\u2013drug interaction liability.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70336","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:06:44Z","timestamp":1788782804000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Net Renal Drug Secretion Critically Requires Significant Contribution of Basal Uptake Transporters: Perspective From Mechanistic Kidney Model Simulation and Integration of Clinical and In\u00a0Vitro Data"],"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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9829-8436","authenticated-orcid":false,"given":"Masatoshi","family":"Tomi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Keio University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Genomembrane Co. 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