Trial reportEuropean journal of clinical pharmacology2013
Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity.
Trial report in European journal of clinical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 37 citations in OpenAlex.
- Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers.British journal of clinical pharmacology · 2014Trial
- Concentration effect relationship of CYP3A inhibition by ritonavir in humans.European journal of clinical pharmacology · 2013Trial
- Mechanisms and Therapeutic Advances of PXR in Metabolic Diseases and Cancer.International journal of molecular sciences · 2025Review
- The Use of Microdosing for In vivo Phenotyping of Cytochrome P450 Enzymes: Where Do We Stand? A Narrative Review.European journal of drug metabolism and pharmacokinetics · 2024Review
- Review
- Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy.Stem cell reports · 2022Article
- Mechanistically Coupled PK (MCPK) Model to Describe Enzyme Induction and Occupancy Dependent DDI of Dabrafenib Metabolism.Pharmaceutics · 2022Article
- Insights into the critical role of the PXR in preventing carcinogenesis and chemotherapeutic drug resistance.International journal of biological sciences · 2022Review
- Dechlorination and demethylation of ochratoxin A enhance blocking activity of PXR activation, suppress PXR expression and reduce cytotoxicity.Toxicology letters · 2020Article
- PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches.Expert opinion on drug metabolism & toxicology · 2020Review
- Rivaroxaban and macitentan can be coadministered without dose adjustment but the combination of rivaroxaban and St John's wort should be avoided.British journal of clinical pharmacology · 2018Article
- SPA70 is a potent antagonist of human pregnane X receptor.Nature communications · 2017Article
- Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.Journal of toxicology · 2017Article
- Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies.British journal of clinical pharmacology · 2015Review
- In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.British journal of pharmacology · 2014Article
- PXR antagonists and implication in drug metabolism.Drug metabolism reviews · 2013Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeThe aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction.
methodsA two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John's wort for 8 days to study the proposed suppression of St John's wort-mediated induction of CYP3A at the transcriptional level. In the second phase, we studied the inhibitory effect of a single dose of ketoconazole directly at the enzyme level during CYP3A induction by St John's wort. Midazolam served as a marker substance of CYP3A activity using an established limited sampling strategy.
resultsAfter 8 days of simultaneous ketoconazole and St John's wort administration, CYP3A-mediated midazolam metabolism was strongly inhibited (81 % decrease in clearance). Following the induction of CYP3A with St John's wort (6.6-fold increase in clearance on day 8), a single dose of ketoconazole strongly inhibited midazolam metabolism to the same degree (82 % decrease in clearance in relation to baseline). An induction of midazolam metabolism was observed after discontinuation of both drugs in both study phases. These results apparently contradict the in vitro results where ketoconazole showed an inhibitory effect on the transcription of CYP3A genes.
conclusionsKetoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John's wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.