{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:20:54Z","timestamp":1774372854565,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HD085887"],"award-info":[{"award-number":["1R01HD085887"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HIV Medicine"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The World Health Organization recommends that all countries adopt dolutegravir\u2010based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug\u2013drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)\u2010mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL<jats:sub>int.app.<\/jats:sub>) and <jats:italic>CYP<\/jats:italic> gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> CYP\u2010mediated CL<jats:sub>int.app.<\/jats:sub> of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CL<jats:sub>int.app.<\/jats:sub>, using liquid chromatography\u2010tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real\u2010time polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CL<jats:sub>int.app.<\/jats:sub> was 22.4\u00a0\u00b1\u00a05.0\u00a0\u03bcL\/min\/10<jats:sup>6<\/jats:sup>\u00a0hepatocytes. Incubation with 43.1\u00a0nM of unbound dolutegravir elevated levonorgestrel CL<jats:sub>int.app.<\/jats:sub> to 31.4\u00a0\u00b1\u00a07.8\u00a0\u00b5L\/min\/10<jats:sup>6<\/jats:sup>\u00a0hepatocytes (<jats:italic>P\u00a0<\/jats:italic>=\u00a00.168), while 142.23\u00a0nM increased levonorgestrel CL<jats:sub>int.app.<\/jats:sub> to 37.0\u00a0\u00b1\u00a02.9\u00a0\u00b5L\/min\/10<jats:sup>6<\/jats:sup>\u00a0hepatocytes (<jats:italic>P\u00a0<\/jats:italic>=\u00a00.012). Unbound dolutegravir \u2265\u00a0431\u00a0nM induced expression of <jats:italic>CYP3A4<\/jats:italic> (\u2265\u00a0two\u2010fold) in a dose\u2010dependent manner, while 1.44\u00a0\u03bcM of unbound dolutegravir induced <jats:italic>CYP2B6<\/jats:italic> expression 2.2\u00a0\u00b1\u00a00.3\u2010fold (<jats:italic>P\u00a0<\/jats:italic>=\u00a00.0004).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, this <jats:italic>in vitro<\/jats:italic> study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non\u2010CYP3A enzymes. The observed <jats:italic>in vitro<\/jats:italic> dolutegravir\u2013levonorgestrel drug\u2013drug interaction should be further examined in clinical studies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hiv.13136","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T10:27:39Z","timestamp":1627640859000},"page":"898-906","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>In\u00a0vitro<\/i> assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel"],"prefix":"10.1111","volume":"22","author":[{"given":"Owain","family":"Roberts","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics Institute of Systems, Molecular and Integrative Biology University of Liverpool Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Kinvig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics Institute of Systems, Molecular and Integrative Biology University of Liverpool Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Owen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics Institute of Systems, Molecular and Integrative Biology Materials Innovation Factory University of Liverpool Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Lamorde","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute College of Health Sciences Makerere University Kampala Uganda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3539-7867","authenticated-orcid":false,"given":"Marco","family":"Siccardi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics Institute of Systems, Molecular and Integrative Biology University of 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