{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T11:39:52Z","timestamp":1767008392671,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"The Ohio State University Comprehensive Cancer Center Pelotonia Foundation (to SH) and the National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA238946"],"award-info":[{"award-number":["R01CA238946"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Exemestane, a steroidal aromatase inhibitor prescribed for post-menopausal women with estrogen receptor-positive breast cancer, is associated with debilitating musculoskeletal side effects and exhibits considerable interindividual variability in systemic exposure. Although exemestane is metabolized mainly by cytochrome P-450 3A4, the contribution of this metabolic pathway to the elimination of exemestane and its drug\u2013drug interaction liabilities remains uncertain. Here, we developed a novel quantification method for exemestane and applied it to evaluate the role of CYP3A-mediated metabolism in the pharmacokinetics of exemestane using wild-type and Cyp3a-deficient mice. Liquid chromatography\u2013mass spectrometry was used to quantify exemestane in selective reaction monitoring (SRM) mode, in which precursor ion and fragment ion data were obtained simultaneously. Validation results demonstrated that the developed method was accurate and precise, and sufficiently sensitive to be applied to murine pharmacokinetic studies involving serial blood sampling strategies. Although in vitro studies indicate that exemestane undergoes extensive metabolism in the liver to inactive metabolites by CYP3A4, complete Cyp3a deficiency in mice did not influence the systemic exposure to exemestane. This unequivocal evidence from genetic approaches using preclinical mouse models confirms that the potential for such DDI liabilities is very low. Our newly developed method provides a robust platform for further pharmacokinetic studies with exemestane in mice to delineate DDI liabilities and define the mechanisms of elimination.<\/jats:p>","DOI":"10.3390\/molecules30071440","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T12:01:50Z","timestamp":1742817710000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Determination and Disposition of the Aromatase Inhibitor Exemestane in CYP3A-Deficient Mice"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-7870","authenticated-orcid":false,"given":"Hanieh","family":"Taheri","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eman","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2660-6644","authenticated-orcid":false,"given":"Alex","family":"Sparreboom","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9806-7734","authenticated-orcid":false,"given":"Shuiying","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"889","DOI":"10.2165\/00003495-200969070-00007","article-title":"Exemestane: A review of its use in postmenopausal women with breast cancer","volume":"69","author":"Deeks","year":"2009","journal-title":"Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2000081","DOI":"10.1002\/ardp.202000081","article-title":"Aromatase inhibitors: Role in postmenopausal breast cancer","volume":"353","author":"Kharb","year":"2020","journal-title":"Arch. 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