{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:17:49Z","timestamp":1760145469243,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T00:00:00Z","timestamp":1722556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health","award":["75N94020D00003"],"award-info":[{"award-number":["75N94020D00003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>11\u03b2-Methyl-19-nortestosterone dodecylcarbonate (11\u03b2-MNTDC) is a prodrug of 11\u03b2-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11\u03b2-MNTDC exhibits an ~200-fold lower serum concentration of 11\u03b2-MNT compared to 11\u03b2-MNTDC, resulting in the poor bioavailability of 11\u03b2-MNT. To elucidate the role of the first-pass metabolism of 11\u03b2-MNT in its poor bioavailability, we determined the biotransformation products of 11\u03b2-MNT and its prodrugs in human in vitro models. 11\u03b2-MNT and its two prodrugs 11\u03b2-MNTDC and 11\u03b2-MNT undecanoate (11\u03b2-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography\u2013high resolution tandem mass spectrometry analysis, which identified ten 11\u03b2-MNT biotransformation products with dehydrogenated and glucuronidation (11\u03b2-MNTG) metabolites being the major metabolites. However, 11\u03b2-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11\u03b2-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11\u03b2-MNTG formation. This was further supported by a strong correlation (R2 &gt; 0.78) between 11\u03b2-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11\u03b2-MNT and its prodrugs are rapidly metabolized to 11\u03b2-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug.<\/jats:p>","DOI":"10.3390\/pharmaceutics16081032","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T13:14:42Z","timestamp":1722604482000},"page":"1032","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of the Biotransformation Pathways of a Potential Oral Male Contraceptive, 11\u03b2-Methyl-19-Nortestosterone (11\u03b2-MNT) and Its Prodrugs: An In Vitro Study Highlights the Contribution of Polymorphic Intestinal UGT2B17"],"prefix":"10.3390","volume":"16","author":[{"given":"Namrata","family":"Bachhav","sequence":"first","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Washington State University (WSU), Spokane, WA 99202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7248-6714","authenticated-orcid":false,"given":"Dilip Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Washington State University (WSU), Spokane, WA 99202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-9340","authenticated-orcid":false,"given":"Diana L.","family":"Blithe","sequence":"additional","affiliation":[{"name":"Contraceptive Development Program, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 1 Center Dr, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8567-2065","authenticated-orcid":false,"given":"Min S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Contraceptive Development Program, Division of Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 1 Center Dr, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhagwat","family":"Prasad","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Washington State University (WSU), Spokane, WA 99202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e380","DOI":"10.1016\/S2214-109X(18)30029-9","article-title":"Global, Regional, and Subregional Trends in Unintended Pregnancy and Its Outcomes from 1990 to 2014: Estimates from a Bayesian Hierarchical Model","volume":"6","author":"Bearak","year":"2018","journal-title":"Lancet Glob. 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