{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:54:53Z","timestamp":1792101293857,"version":"4.4.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["Grant R01HD102786"],"award-info":[{"award-number":["Grant R01HD102786"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018\/05616-3 2019\/03429-4 2021\/10292-5"],"award-info":[{"award-number":["2018\/05616-3 2019\/03429-4 2021\/10292-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Pregnancy results in significant changes in drug pharmacokinetics (PK). While previous studies have elucidated the impact of pregnancy-related hormones (PRH) on mRNA or protein expression and activity of major hepatic metabolizing enzymes, their effect on hepatic drug transporters remains largely unexplored. Therefore, we investigated the effect of a cocktail of PRH on the mRNA expression and activity of hepatic transporters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plated human hepatocytes (PHH) from 3 premenopausal donors were incubated, in triplicate, for 72\u00a0h, with vehicle (DMSO &amp;lt; 0.01%), rifampin (10\u00a0\u03bcM; positive control) or a cocktail of PRH consisting of estrone, estradiol, estriol, estetrol, progesterone, cortisol, testosterone, oxytocin, and placental growth hormone. The PRH concentrations replicated 0.1\u00d7, 1\u00d7, or 10\u00d7 of the plasma concentrations of these hormones observed during each of the three trimesters of pregnancy. After treatment, mRNA expression (quantified by qPCR) of hepatic influx and efflux transporters as well as the activity of influx transporters was quantified (uptake of a selective substrate \u00b1 corresponding transporter inhibitor). The data were expressed relative to that in the control (vehicle) group. Significance was evaluated by ANOVA (followed by Dunn\u2019s multiple comparisons) or unpaired <jats:italic>t<\/jats:italic>-test when the within-lot data were analyzed, or repeated measures ANOVA (followed by Dunn\u2019s multiple comparisons) or paired <jats:italic>t<\/jats:italic>-test when data from all 3 lots were analyzed (<jats:italic>p<\/jats:italic> &amp;lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Discussion<\/jats:title><jats:p>In general, a) PRH cocktails significantly induced transporter mRNA expression in the following order OAT2 \u2248 NTCP \u2248 OCT1 &amp;gt; OATP2B1 and repressed mRNA expression in the following order OATP1B3 &amp;gt; OATP1B1; b) these changes translated into significant induction of OAT2 (T1-T3) and NTCP (T2-T3, in only two lots) activity at the 1\u00d7 PRH concentration. Compared with the influx transporters, the induction of mRNA expression of efflux transporters was modest, with mRNA expression of MRP2 and BSEP being induced the most.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Once these data are verified through <jats:italic>in vivo<\/jats:italic> probe drug PK studies in pregnancy, they can be populated into physiologically based pharmacokinetic (PBPK) models to predict, for all trimesters of pregnancy, transporter-mediated clearance of any drug that is a substrate of the affected transporters.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1440010","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T04:28:31Z","timestamp":1723004911000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["The effect of pregnancy-related hormones on hepatic transporters: studies with premenopausal human hepatocytes"],"prefix":"10.3389","volume":"15","author":[{"given":"Jhohann Richard de Lima","family":"Benzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yik Pui","family":"Tsang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jashvant D.","family":"Unadkat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"16504","DOI":"10.1074\/jbc.M109.072140","article-title":"Inhibition of Na+-taurocholate co-transporting polypeptide-mediated bile acid transport by cholestatic sulfated progesterone metabolites","volume":"285","author":"Abu-Hayyeh","year":"2010","journal-title":"J. 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