{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:50:24Z","timestamp":1788871824265,"version":"build-2803163510"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,10,20]],"date-time":"2014-10-20T00:00:00Z","timestamp":1413763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2014,11]]},"abstract":"\n Aims<\/jats:title>\n \n This study aimed to assess changes in the plasma concentrationss of 4\u03b2\u2010hydroxycholesterol (4\u03b2\n HC<\/jats:styled-content>\n ) against intravenous (i.v.) and oral midazolam (\n MDZ<\/jats:styled-content>\n ) pharmacokinetics (\n PK<\/jats:styled-content>\n ) after administration of a potent\n CYP3A<\/jats:styled-content>\n inhibitor [ketoconazole (\n KETO<\/jats:styled-content>\n )] and inducer [rifampicin (\n RIF<\/jats:styled-content>\n )].\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Thirty\u2010two healthy subjects (\n HS<\/jats:styled-content>\n ) were allocated into three groups of 12 each in\n KETO<\/jats:styled-content>\n and\n RIF<\/jats:styled-content>\n and 10 in a placebo group (\n PLB<\/jats:styled-content>\n ). All\n HS<\/jats:styled-content>\n were randomized to receive oral and i.v.\n MDZ<\/jats:styled-content>\n on day 1 or 2 and on day 15 or 16 after receiving\n RIF<\/jats:styled-content>\n (600\u2009mg\n once daily<\/jats:styled-content>\n ),\n KETO<\/jats:styled-content>\n (400\u2009mg once daily) or\n PLB<\/jats:styled-content>\n for 2 weeks. Subjects were followed until day 30. The effect of treatments on 4\u03b2\n HC<\/jats:styled-content>\n was assessed by analyzing % change from baseline using a linear spline mixed effects model.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Compared with\n PLB<\/jats:styled-content>\n ,\n KETO<\/jats:styled-content>\n decreased 4\u03b2\n HC<\/jats:styled-content>\n mean values up to 13% (\n P<\/jats:italic>\n = 0.003) and\n RIF<\/jats:styled-content>\n increased 4\u03b2\n HC<\/jats:styled-content>\n mean values up to 220% (\n P<\/jats:italic>\n < 0.001). Within 14 days of stopping\n KETO<\/jats:styled-content>\n and\n RIF<\/jats:styled-content>\n , 4\u03b2\n HC<\/jats:styled-content>\n had either returned to baseline (\n KETO<\/jats:styled-content>\n ) or was still returning to baseline (\n RIF<\/jats:styled-content>\n ). Compared with baseline, mean oral\n MDZ AUC<\/jats:styled-content>\n increased by 11\u2010fold (90%\n CI<\/jats:styled-content>\n ranging from 9\u2010fold to 13\u2010fold increase) and decreased by 92% (90%\n CI<\/jats:styled-content>\n ranging from 90% to 95% decrease) after\n KETO<\/jats:styled-content>\n and\n RIF<\/jats:styled-content>\n , respectively. Similar trends were observed for 6\u03b2\u2010hydroxycortisol\u2009:\u2009cortisol (6\u03b2\n HCL<\/jats:styled-content>\n \u2009:\u2009\n CL<\/jats:styled-content>\n ) urinary ratios.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Changes in plasma 4\u03b2\n HC<\/jats:styled-content>\n can be utilized as a surrogate for\n MDZ PK<\/jats:styled-content>\n after multiple doses of potent\n CYP3A<\/jats:styled-content>\n inducers. There is a more limited dynamic range for 4\u03b2\n HC<\/jats:styled-content>\n for assessment of potential\n CYP3A<\/jats:styled-content>\n inhibitors. 4\u03b2\n HC<\/jats:styled-content>\n is a valuable tool for the assessment of potential\n CYP3A<\/jats:styled-content>\n inducers in early drug development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bcp.12425","type":"journal-article","created":{"date-parts":[[2014,5,16]],"date-time":"2014-05-16T07:11:10Z","timestamp":1400224270000},"page":"1122-1134","source":"Crossref","is-referenced-by-count":84,"title":["Validation of 4\u03b2\u2010hydroxycholesterol and evaluation of other endogenous biomarkers for the assessment of\n CYP3A<\/scp>\n activity in healthy subjects"],"prefix":"10.1111","volume":"78","author":[{"given":"Sreeneeranj","family":"Kasichayanula","sequence":"first","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Boulton","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Lin","family":"Luo","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb Princeton NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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