{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T06:58:33Z","timestamp":1785308313280,"version":"3.55.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    The accurate prediction of clinical drug\u2013drug interactions (DDIs) in modeling analysis relies on the fraction of metabolism and transport of the substrate drugs and on the inhibitory potency and plasma exposure of index inhibitors. Fluconazole is frequently used as a clinical index inhibitor of cytochrome P450 (CYP) 2C9 and CYP3A4 to assess DDI liabilities involving these CYP enzymes. It also inhibits uridine diphosphate glucuronosyltransferase (UGT) 2B7 and exhibits gender-dependent pharmacokinetics (PK). The currently available model profile of fluconazole does not account for these population-specific PK variations. Therefore, extrapolating from one fluconazole DDI dataset to another remains questionable when it is used as an index inhibitor. In the present study, a physiologically based pharmacokinetic (PBPK) model of fluconazole was developed using PK data from male and female subjects. A minimal PBPK model with advanced dissolution, absorption, and metabolism (ADAM) for fluconazole was built in the Simcyp Simulator (V22). The base model from the Simcyp compound library captured fluconazole plasma profiles following oral administration only in male subjects, but not in female subjects. The volume of distribution at steady state (V\n                    <jats:sub>ss<\/jats:sub>\n                    ) of fluconazole is close to the total body water volume, which can contribute to differences in plasma profiles between male and female subjects. Therefore, V\n                    <jats:sub>ss<\/jats:sub>\n                    in female subjects was optimized by curve fitting. The total clearance (CL) value in female subjects was also adjusted to reflect the similar fluconazole elimination half-life (t\n                    <jats:sub>1\/2<\/jats:sub>\n                    ) between male and female subjects. The plasma profiles of fluconazole in the general population were captured well when the predicted mean V\n                    <jats:sub>ss<\/jats:sub>\n                    and total CL were calibrated by the proportion of female subjects. The developed model was further validated by simulating reported clinical DDI studies with fluconazole. Using the refined PBPK model, the inhibitory constants (Ki) for fluconazole against CYP2C9 and UGT2B7 were optimized. The final fluconazole model captured the precipitant DDIs with midazolam (CYP3A probe substrate), tolbutamide (CYP2C9 probe substrate), omeprazole (CYP2C19 probe substrate), and zidovudine (UGT2B7 probe substrate), indicating that the refined fluconazole PBPK model in the present study can accurately predict clinical DDIs across studies in different populations with diverse gender mixes.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1849886","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:58:52Z","timestamp":1785304732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiologically based pharmacokinetic modeling of fluconazole: interpretation of gender-dependent pharmacokinetics and cytochrome P450 inhibition"],"prefix":"10.3389","volume":"17","author":[{"given":"Kazuya","family":"Ishida","sequence":"first","affiliation":[{"name":"Drug Metabolism, Gilead Sciences, Inc.","place":["Foster, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakshit Sanjay","family":"Tanna","sequence":"additional","affiliation":[{"name":"Drug Metabolism, Gilead Sciences, Inc.","place":["Foster, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Yang","sequence":"additional","affiliation":[{"name":"Drug Metabolism, Gilead Sciences, Inc.","place":["Foster, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurong","family":"Lai","sequence":"additional","affiliation":[{"name":"Drug Metabolism, Gilead Sciences, Inc.","place":["Foster, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/cpdd.852","article-title":"Assessment of pharmacokinetic interaction between letermovir and fluconazole in healthy participants","volume":"10","author":"Adedoyin","year":"2021","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s002280050223","article-title":"Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam","volume":"51","author":"Ahonen","year":"1997","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/j.1552-4604.1991.tb03718.x","article-title":"Induction of fluconazole metabolism by rifampin: in vivo study in humans","volume":"31","author":"Apseloff","year":"1991","journal-title":"J. Clin. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1177\/0091270010370588","article-title":"Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants","volume":"51","author":"Bavisotto","year":"2011","journal-title":"J. Clin. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/S0090-9556(25)07369-6","article-title":"Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies","volume":"24","author":"Black","year":"1996","journal-title":"Drug Metabolism Dispos."},{"key":"B6","first-page":"1041","article-title":"Increased cyclosporine levels as a result of simultaneous fluconazole and cyclosporine therapy in renal transplant recipients: a double-blind, randomized pharmacokinetic and safety study","volume":"23","author":"Canafax","year":"1991","journal-title":"Transpl. Proc."},{"key":"B7","doi-asserted-by":"publisher","first-page":"851","DOI":"10.2165\/00044011-200727120-00007","article-title":"Gender differences in the oral pharmacokinetics of fluconazole","volume":"27","author":"Carrasco-Portugal","year":"2007","journal-title":"Clin. Drug Investig."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1046\/j.1523-1755.2001.00741.x","article-title":"Heymsfield SB and siervogel RM (2001) total body water reference values and prediction equations for adults","volume":"59","author":"Chumlea","year":"2001","journal-title":"Kidney Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"10","DOI":"10.2165\/00003088-199324010-00002","article-title":"Clinical pharmacokinetics of fluconazole","volume":"24","author":"Debruyne","year":"1993","journal-title":"Clin. Pharmacokinet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3181\/0802-RM-59","article-title":"MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells","volume":"233","author":"Eilers","year":"2008","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S0090-9556(24)15274-9","article-title":"Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression","volume":"27","author":"Gibbs","year":"1999","journal-title":"Drug Metabolism Dispos."},{"key":"B14","first-page":"129","article-title":"Effect of age and sex on glomerular filtration rate measured by 51Cr-EDTA","volume":"25","author":"Gross","year":"1992","journal-title":"Braz J. Med. Biol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s11883-017-0682-x","article-title":"Clinical guidance for managing statin and antimicrobial drug-drug interactions","volume":"19","author":"Hylton Gravatt","year":"2017","journal-title":"Curr. Atheroscler. Rep."},{"key":"B16","volume-title":"ICH Harmonized Guideline Drug Interaction Studies M12","year":"2024"},{"key":"B17","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1124\/dmd.107.018382","article-title":"The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substrate-dependent: an in vitro-in vivo evaluation","volume":"36","author":"Isoherranen","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"B18","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1002\/bdd.291","article-title":"Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers","volume":"23","author":"Kang","year":"2002","journal-title":"Biopharm. Drug Dispos."},{"key":"B19","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1046\/j.1365-2125.1999.00965.x","article-title":"Loss of blood pressure control on withdrawal of fluconazole during nifedipine therapy","volume":"47","author":"Kremens","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/S0090-9556(25)07368-4","article-title":"Inhibition of the human cytochrome P450-dependent metabolism of warfarin by fluconazole: in vitro studies","volume":"24","author":"Kunze","year":"1996","journal-title":"Drug Metabolism Dispos."},{"key":"B21","doi-asserted-by":"publisher","first-page":"S327","DOI":"10.1093\/clinids\/12.supplement_3.s327","article-title":"Drug interactions with fluconazole","volume":"12","author":"Lazar","year":"1990","journal-title":"Rev. Infect. Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1124\/pharmrev.120.000206","article-title":"Sex- and gender-based pharmacological response to drugs","volume":"73","author":"Mauvais-Jarvis","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"B23","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/S0009-9236(98)90165-5","article-title":"Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole","volume":"63","author":"Neuvonen","year":"1998","journal-title":"Clin. Pharmacol. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1007\/s00125-003-1034-7","article-title":"Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide","volume":"46","author":"Niemi","year":"2003","journal-title":"Diabetologia"},{"key":"B25","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1097\/00000539-199603000-00015","article-title":"The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam","volume":"82","author":"Olkkola","year":"1996","journal-title":"Anesth. Analg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1592\/phco.2005.25.10.1310","article-title":"Pharmacokinetics of intravenously administered levofloxacin in men and women","volume":"25","author":"Overholser","year":"2005","journal-title":"Pharmacotherapy"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.2147\/DDDT.S131797","article-title":"Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer","volume":"11","author":"Park","year":"2017","journal-title":"Drug Des. Devel Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1002\/cphy.c170039","article-title":"Intestinal nucleoside transporters: function, expression, and regulation","volume":"8","author":"Pastor-Anglada","year":"2018","journal-title":"Compr. Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1093\/infdis\/169.5.1103","article-title":"Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus","volume":"169","author":"Sahai","year":"1994","journal-title":"J. Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"107","DOI":"10.2165\/00003088-200342020-00001","article-title":"The influence of sex on pharmacokinetics","volume":"42","author":"Schwarz","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"143","DOI":"10.2165\/00003088-200948030-00001","article-title":"Sex differences in pharmacokinetics and pharmacodynamics","volume":"48","author":"Soldin","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1592\/phco.19.6.442.31044","article-title":"Effect of gender on the pharmacokinetics of ofloxacin","volume":"19","author":"Sowinski","year":"1999","journal-title":"Pharmacotherapy"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1128\/aac.34.10.2032","article-title":"Effect of oral antacid administration on the pharmacokinetics of oral fluconazole","volume":"34","author":"Thorpe","year":"1990","journal-title":"Antimicrob. Agents Chemother."},{"key":"B35","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/j.1365-2125.1990.tb03623.x","article-title":"An assessment of the effects of impaired renal function and haemodialysis on the pharmacokinetics of fluconazole","volume":"29","author":"Toon","year":"1990","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1111\/j.1365-2125.2006.02588.x","article-title":"Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation","volume":"61","author":"Uchaipichat","year":"2006","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1007\/s00415-004-0407-2","article-title":"Clinical evidence of fluconazole-induced carbamazepine toxicity","volume":"251","author":"Ulivelli","year":"2004","journal-title":"J. Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3612","DOI":"10.1210\/jcem.82.11.4388","article-title":"Metabolic effects and pharmacokinetics of a growth hormone pulse in healthy adults: relation to age, sex, and body composition","volume":"82","author":"Vahl","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B40","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1046\/j.1365-2125.1996.45111.x","article-title":"Effect of fluconazole dose on the extent of fluconazole\u2010triazolam interaction","volume":"42","author":"Varhe","year":"2003","journal-title":"Br. J. Clin. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/S0090-9556(25)09188-3","article-title":"Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19","volume":"24","author":"Wienkers","year":"1996","journal-title":"Drug Metab. Dispos."},{"key":"B42","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1080\/17425255.2022.2112175","article-title":"Important roles of transporters in the pharmacokinetics of anti-viral nucleoside\/nucleotide analogs","volume":"18","author":"Yang","year":"2022","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/BF00199879","article-title":"Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole","volume":"46","author":"Zimmermann","year":"1994","journal-title":"Eur. J. Clin. Pharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1849886\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T05:58:54Z","timestamp":1785304734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1849886\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":39,"alternative-id":["10.3389\/fphar.2026.1849886"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1849886","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"article-number":"1849886"}}