{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T03:39:47Z","timestamp":1787974787017,"version":"build-2784847793"},"reference-count":55,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100015339","name":"ACCP Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015339","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gender\u2010affirming testosterone therapy is one part of the standard of care for more than 1 million transgender adults in the United States. Testosterone therapy may influence the activities of drug\u2010metabolizing enzymes and transporters, but knowledge about its effect on the pharmacokinetics of other medications is limited. We determined the effects of gender\u2010affirming testosterone therapy on apparent cytochrome P450 (CYP) 3A and P\u2010glycoprotein activities using midazolam and digoxin as model probe substrates among transgender adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This was a longitudinal (pre\u2010treatment and with concomitant testosterone therapy), prospective, non\u2010randomized, open\u2010label, three\u2010phase probe substrate study. Eligible participants started testosterone therapy based on clinical need. Participants received one oral dose of midazolam 2\u2009mg and digoxin 0.25\u2009mg (simultaneous dosing) under fasted conditions before starting gender\u2010affirming testosterone therapy (baseline), and at 1\u2010month and 3\u2010months on gender\u2010affirming testosterone therapy. Midazolam, 1\u2032\u2010hydroxymidazolam, 4\u2010hydroxymidazolam, digoxin, and total testosterone concentrations were determined by liquid chromatography\u2013tandem mass spectrometry assays. We estimated single\u2010dose pharmacokinetic parameters of midazolam, its metabolites, and digoxin using standard noncompartmental methods. Pharmacokinetic parameters were compared with testosterone therapy at 1\u2010month and 3\u2010months to baseline as geometric mean ratios (90% confidence intervals) and paired t\u2010tests after log transformation. A\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.025 was considered significant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 14 participants (mean age: 24\u2009\u00b1\u20093\u2009years; weight: 82.9\u2009\u00b1\u200920.9\u2009kg; race\/ethnicity: 71% White, non\u2010Hispanic, 14% Hispanic, 7% Asian, 7% mixed race), nine participants started weekly testosterone injections (20\u2009mg to 80\u2009mg once weekly) and five started daily transdermal testosterone applications (12.5\u2009mg to 50\u2009mg once daily gel or cream, 2\u2009mg daily patch). Mean total testosterone concentrations at 3\u2009months increased more than 20\u2010fold from baseline concentrations (25\u2009\u00b1\u20097\u2009ng\/dL to 507\u2009\u00b1\u2009263\u2009ng\/dL). Geometric mean midazolam and metabolite pharmacokinetic parameters and digoxin parameters were not significantly different at baseline and with testosterone therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Gender\u2010affirming testosterone therapy did not significantly affect CYP3A or P\u2010glycoprotein activities. Gender\u2010affirming testosterone therapy may have minimal effects on the pharmacokinetics of other medications that are substrates of CYP3A and P\u2010glycoprotein. Caution may be warranted for medications with a narrow therapeutic index.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/phar.70093","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T17:55:17Z","timestamp":1766771717000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effect of Testosterone Therapy on Cytochrome P450 3A and P\u2010Glycoprotein Activities Using Midazolam and Digoxin as Probe Substrates Among Transgender Adults"],"prefix":"10.1002","volume":"46","author":[{"given":"Michiko","family":"Hunter","sequence":"first","affiliation":[{"name":"Department of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Coig","sequence":"additional","affiliation":[{"name":"Department of Pharmacy University of Washington  Seattle Washington 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