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The single nucleotide polymorphism\n                      <jats:italic>*3<\/jats:italic>\n                      is significantly associated with the increased exposure of CYP2C9 substrates. In addition, metabolic enzyme inhibitors such as fluconazole may also increase the drug exposure of CYP2C9 substrates. However, the interactions between the impact of\n                      <jats:italic>CYP2C9<\/jats:italic>\n                      genotypes and the inhibitory effects of interacting drugs with respect to the CYP2C9 mediated fraction of metabolism (\n                      <jats:italic>f<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>m<\/jats:italic>\n                      <\/jats:sub>\n                      ) are rarely investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approaches<\/jats:title>\n                    <jats:p>\n                      Using tolbutamide, flurbiprofen and ketoprofen as representative substrates with high, medium and low CYP2C9 mediated\n                      <jats:italic>f<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>m<\/jats:italic>\n                      <\/jats:sub>\n                      , respectively, an open\u2010label, block\u2010randomized, crossover clinical drug\u2013drug interaction study was conducted using fluconazole as a representative interacting drug. A pharmacometric model\u2010based analysis was subsequently performed to assess the impact of\n                      <jats:italic>CYP2C9<\/jats:italic>\n                      genotypes on the absolute and fractional changes in apparent clearance (CL\/F) with fluconazole co\u2010administration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Our study shows tolbutamide and flurbiprofen, but not ketoprofen, exhibit\n                      <jats:italic>CYP2C9<\/jats:italic>\n                      genotype\u2010dependency on both absolute and fractional changes in CL\/F following the fluconazole co\u2010administration. An interesting finding is the\n                      <jats:italic>CYP2C9<\/jats:italic>\n                      genotype\u2010dependency on fluconazole induced fractional CL\/F changes is more pronounced in a CYP2C9 substrate with medium CYP2C9 mediated\n                      <jats:italic>f<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>m<\/jats:italic>\n                      <\/jats:sub>\n                      , in comparison to a CYP2C9 substrate with high or low CYP2C9 mediated\n                      <jats:italic>f<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>m<\/jats:italic>\n                      <\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>Our study provides quantitative insights into the genotype\u2010dependent exposure changes of probe drugs with varying CYP2C9 metabolic contributions following the co\u2010administration of fluconazole, highlighting the role of CYP2C9 metabolic contributions in guiding the precision dosing of CYP2C9 substrates.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70337","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:40:01Z","timestamp":1769060401000},"page":"2482-2496","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A model\u2010based analysis of the CYP2C9 genotype effects on fluconazole inhibition using flurbiprofen, ketoprofen and tolbutamide as probe drugs"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7493-4784","authenticated-orcid":false,"given":"Shen","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3914-9534","authenticated-orcid":false,"given":"Darcy R.","family":"Flora","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mutaz M.","family":"Jaber","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, College of Pharmacy University of Minnesota  Minneapolis Minnesota USA"},{"name":"Gilead Sciences, Inc.  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