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Although 4\u03b2-hydroxycholesterol (4\u03b2OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4\u03b2OHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients\u00a0with a wide body weight range.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200996; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4\u03b2OHC and midazolam concentrations, and liver (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200956) and jejunal (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200938) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5\u00a0mg) and intravenous (1.0\u00a0mg) midazolam.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      4\u03b2OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.53,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), and hepatic CYP3A4 concentrations (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.30,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.027), but not with intestinal CYP3A4 concentrations (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.18,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.28) or intestinal microsomal CYP3A4 activity (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.15,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.53). 4\u03b2OHC concentrations correlated weakly with midazolam absolute bioavailability (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u2009\u2212\u20090.23,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.027) and apparent oral clearance (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u20090.28,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.008), but not with systemic clearance (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u2009=\u2009\u2009\u2212\u20090.03,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.81).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that 4\u03b2OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4\u03b2OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>Clinical.Trials.gov identifier: NCT02386917.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00228-022-03336-9","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T01:02:31Z","timestamp":1654045351000},"page":"1289-1299","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Correlations between 4\u03b2-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range"],"prefix":"10.1007","volume":"78","author":[{"given":"Kine","family":"Eide Kvitne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Hole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Krogstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit Malene","family":"Wollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Wegler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line K.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens K.","family":"Hertel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Artursson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommy B.","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rune","family":"Sandbu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8ran","family":"Hjelmes\u00e6th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Skovlund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hege","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Jansson-L\u00f6fmark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"\u00c5sberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Espen","family":"Molden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Robertsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"issue":"1","key":"3336_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","volume":"138","author":"UM Zanger","year":"2013","unstructured":"Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. 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