{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:16:58Z","timestamp":1790612218889,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"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;amp; Syst Pharma"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The gut microbiome can contribute to drug metabolism and significantly influence pharmacokinetic (PK) behavior. Sulfasalazine is well\u2010known to be metabolized by gut bacterial azoreductases into sulfapyridine and mesalamine. Despite in\u00a0vitro and in\u00a0vivo evidence of the gut microbiome's role in drug metabolism, quantitative predictions of its impact on drug PK are lacking. To address this gap, we used sulfasalazine and its metabolites as a case example to build a translational modeling framework to predict the extent of gut microbiome\u2010mediated drug metabolism and subsequent PK of the metabolites. First, sulfasalazine conversion kinetics was measured in\u00a0vitro using pooled human fecal homogenate incubation. In\u00a0vitro\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    was 650.5 and 200.9\u2009pmol\/min\/mg feces, and\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>m<\/jats:sub>\n                    was 3648 and 1605\u2009\u03bcM for sulfapyridine and mesalamine formation, respectively. Based on colon and feces bacterial counts from nine healthy humans, a ratio of 0.47 was used to scale in\u00a0vitro fecal\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    to the colon level. Second, physiologically\u2010based pharmacokinetic (PBPK) models for sulfasalazine, sulfapyridine, and mesalamine were built in Simcyp and verified to predict their oral PK when dosed directly. Lastly, sulfapyridine or mesalamine PK after dosing sulfasalazine was predicted by linking the parent and metabolite PBPK models with colon luminal metabolism kinetics. The observed sulfapyridine and mesalamine PK after dosing sulfasalazine were predicted with weighted average fold\u2010errors of 1.21, 1.22, and 1.05 for\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ,\n                    <jats:italic>T<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    , and AUC, respectively. Overall, this in\u00a0vitro to in\u00a0vivo translation and modeling framework provides valuable insights for quantitatively predicting the in\u00a0vivo impact of gut microbiome\u2010mediated drug metabolism.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70246","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T08:55:07Z","timestamp":1775638507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Translational Modeling of Gut Microbiome\u2010Mediated Drug Metabolism: A Case Example of Sulfasalazine"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3376-7164","authenticated-orcid":false,"given":"Lisa","family":"Cheng","sequence":"first","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Genentech, Inc.  South San Francisco California USA"},{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver British Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Cai","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Auster","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungjoon","family":"Cho","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Keir","sequence":"additional","affiliation":[{"name":"Human Pathobiology and OMNI Reverse Translation, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horace","family":"Rhee","sequence":"additional","affiliation":[{"name":"Early Clinical Development, OMNI, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bennett","family":"Kapili","sequence":"additional","affiliation":[{"name":"Envivo Bio, Inc.  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dari","family":"Shalon","sequence":"additional","affiliation":[{"name":"Envivo Bio, Inc.  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoran","family":"Ning","sequence":"additional","affiliation":[{"name":"Drug Metabolism and Pharmacokinetics, Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002533"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2008.07.009"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101291\u20103"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2023.07.002"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejm198110013051403"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235872"},{"key":"e_1_2_9_8_1","unstructured":"\u201cAzulfidine Sulfasalazine Tablets Label \u201d2022 https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/007073s133lbl.pdf."},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3565(25)29238-2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(79)90277-4"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010023\u201003478\u20100"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00129\u201019"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.70035"},{"key":"e_1_2_9_14_1","unstructured":"K. G.Ma\u00eflysDe Sousa Mendes S.Neuhoff andI.Gardner \u201cSulfasalazine a BCRP Probe Substrate: Development of a Physiologically Based Pharmacokinetic (PBPK) Model \u201dPresented at: Marbachcastle DDI workshop 27th to 29th May 2018 https:\/\/www.certara.com\/poster\/sulfasalazine\u2010a\u2010bcrp\u2010probe\u2010substrate\u2010development\u2010of\u2010a\u2010physiologically\u2010based\u2010pharmacokinetic\u2010pbpk\u2010model\/."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476\u20105381.2012.01887.x"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.24366"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0954\u20106820.1941.tb09092.x"},{"issue":"4","key":"e_1_2_9_18_1","first-page":"597","article-title":"The Pharmacokinetics of Sulfapyridine and Its N4\u2010Acetyl\u2010, and Hydroxy Metabolites in Man","volume":"1","author":"Hekster Y. 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