{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:01:19Z","timestamp":1790226079059,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"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":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Reliable endogenous biomarkers for assessing CYP3A activity and clinical drug\u2013drug interaction (DDI) risk remain limited. We characterized global metabolomic changes following itraconazole treatment in a fixed\u2010sequence DDI study (11 healthy volunteers) to identify novel CYP3A endogenous biomarkers. Untargeted metabolomic analysis identified 58 plasma metabolites that were significantly modulated (changed by &gt;\u20091.5\u2010fold or &lt;\u20090.67\u2010fold,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05), highlighting the dynamic and systemic impact of CYP3A inhibition on the human metabolome. Bile acids represented the most prominently affected analytes, whereas changes were also observed in endocannabinoids, xanthine metabolism, and food\u2010derived metabolites, revealing both on\u2010target and potential off\u2010target effects of itraconazole. For example, plasma levels of endocannabinoidome metabolites such as linoleoyl ethanolamide and N\u2010linoleoylglycine increased by 2.4\u2010 to 6.0\u2010fold (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05), while bile acids including glycoursodeoxycholate (GUDCA) and glycohyocholate (GHCA) decreased by 2.6\u2010 to 12.5\u2010fold (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01) following itraconazole treatment. Targeted quantification was subsequently performed for the bile acids identified from untargeted analysis and the emerging CYP3A biomarkers, 1\u03b2\u2010hydroxy\u2010deoxycholic acid (1\u03b2OH\u2010DCA) and its glycine and taurine conjugates. Notably, GHCA, GUDCA and 1\u03b2OH\u2010DCA conjugates exhibited pronounced reduction in plasma exposure (~10\u2010fold,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001) in the itraconazole treatment group. GHCA exhibited lower inter\u2010individual variability than others. In\u00a0vitro characterization demonstrated CYP3A4\u2010selective hydroxylation of glycochenodeoxycholate to form GHCA, supporting its mechanistic linkage to CYP3A4 activity. Collectively, these findings expand the repertoire of sensitive and mechanistically supported endogenous biomarkers of CYP3A activity. Further evaluation of the newly identified GHCA and emerging bile acid metabolites across diverse CYP3A inhibitors can strengthen their translational utility in DDI risk assessment and drug development.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70489","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:20:11Z","timestamp":1790223611000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Untargeted Metabolomics Reveal New Endogenous Plasma Biomarkers Associated with\n                    <scp>CYP3A<\/scp>\n                    Inhibition in Humans"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8121-8746","authenticated-orcid":false,"given":"Sook Wah","family":"Yee","sequence":"first","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-6517","authenticated-orcid":false,"given":"Eugene P.","family":"Kadar","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5976-3809","authenticated-orcid":false,"given":"Matthew A.","family":"Cerny","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8638-5751","authenticated-orcid":false,"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Pfizer R&amp;D, Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-4397","authenticated-orcid":false,"given":"Lloyd Wei Tat","family":"Tang","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Scott","family":"Obach","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Troutman","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9541-6329","authenticated-orcid":false,"given":"Manthena V. S.","family":"Varma","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics, and Metabolism Pfizer R&amp;D, Pfizer Inc.  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