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Using oral midazolam microdoses (30\u2009\u03bcg), we have investigated CYP3A4 induction by St. John's wort (SJW) in 11 healthy volunteers using low (300\u2009mg\/day containing 7.48\u2009mg hyperforin), therapeutic (900\u2009mg\/day), and supratherapeutic doses of SJW (1800\u2009mg\/day) for 14\u2009days. SJW was then co\u2010administered with rifampin (600\u2009mg\/day) for a further 7\u2009days to evaluate the effect of the combined administration of two inducers. In addition, intravenous midazolam microdoses (10\u2009\u03bcg) were administered before SJW, at SJW 1800\u2009mg\/day, and during administration of the two inducers to assess the hepatic contribution to total induction (semi\u2010simultaneous administration). Administration of SJW increased oral midazolam clearance 1.96\u2010fold (300\u2009mg\/day), 3.86\u2010fold (900\u2009mg\/day), and 5.62\u2010fold (1800\u2009mg\/day), and 17.5\u2010fold after the addition of rifampin. Concurrently, the clearance of intravenous midazolam increased 2.05\u2010fold (1800\u2009mg\/day) and 2.93\u2010fold (SJW\u2009+\u2009rifampin). These results show that rifampin significantly enhances the induction of the highest SJW doses both hepatically and overall and suggest that these metabolic effects occur predominantly in the gut. These findings also suggest that in drug interactions involving strong and moderate enzyme inducers, the perpetrator effects of the strong inducer are decisive for the interaction.<\/jats:p>","DOI":"10.1111\/cts.70007","type":"journal-article","created":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T06:40:20Z","timestamp":1723876820000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dose\u2010dependent induction of <scp>CYP3A<\/scp> activity by St. John's wort alone and in combination with rifampin"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-8806","authenticated-orcid":false,"given":"Nicolas","family":"Hohmann","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Friedrichs","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1698","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Burhenne","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-5194","authenticated-orcid":false,"given":"Antje","family":"Blank","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1783-133X","authenticated-orcid":false,"given":"Gerd","family":"Mikus","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0672-6876","authenticated-orcid":false,"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology, Internal Medicine IX, Medical Faculty of Heidelberg, Heidelberg University Hospital University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2016.1163337"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425250802531767"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.05.008"},{"key":"e_1_2_10_5_1","unstructured":"EMA.Guideline on the investigation of drug interactions.2012. 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