Trial reportThe AAPS journal2016
Urinary 6β-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach.
Trial report in The AAPS journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 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
18 citing papers in PubMed, 38 citations in OpenAlex.
- Interpretation of Pharmacometabolomics Results: Fingerprint of Drug Exposure or Confounder Effects? Insights from a Urinary Metabolomics Study with Voriconazole in Healthy Participants.International journal of molecular sciences · 2026Trial
- Oral absorption of voriconazole is affected by SLCO2B1 c.*396T>C genetic polymorphism in CYP2C19 poor metabolizers.The pharmacogenomics journal · 2020Trial
- Exploratory Evaluation of Solanidine as an Endogenous Marker for CYP2D6-Mediated Drug-Drug-Gene Interactions of Venlafaxine in Koreans.Clinical and translational science · 2026Article
- Deconvoluting Gut Versus Liver Cytochrome P450 3A4 Function: Drug Probes, Biomarkers, and Tissue Biopsy.Journal of clinical pharmacology · 2026Review
- Precision medication based on the evaluation of drug metabolizing enzyme and transporter functions.Precision clinical medicine · 2025Review
- Pharmacokinetics in Pharmacometabolomics: Towards Personalized Medication.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The Role of CYP3A in Health and Disease.Biomedicines · 2022Review
- A semimechanistic population pharmacokinetic and pharmacodynamic model incorporating autoinduction for the dose justification of TAS-114.CPT: pharmacometrics & systems pharmacology · 2022Article
- Studies on CYP3A activity during the menstrual cycle as measured by urinary 6β-hydroxycortisol/cortisol.Pharmacology research & perspectives · 2021Article
- Evaluation of 1β-Hydroxylation of Deoxycholic Acid as a Non-Invasive Urinary Biomarker of CYP3A Activity in the Assessment of Inhibition-Based Drug-Drug Interaction in Healthy Volunteers.Journal of personalized medicine · 2021Article
- Volume of Distribution is Unaffected by Metabolic Drug-Drug Interactions.Clinical pharmacokinetics · 2021Article
- Development and validation of a method for the simultaneous quantification of endogenous steroids metabolized by CYP3A.Translational and clinical pharmacology · 2020Article
- Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans.Frontiers in genetics · 2020Article
- A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates.Frontiers in pharmacology · 2020Review
- Phenotyping of Human CYP450 Enzymes by Endobiotics: Current Knowledge and Methodological Approaches.Clinical pharmacokinetics · 2019Review
- Biomarker Discovery for Cytochrome P450 1A2 Activity Assessment in Rats, Based on Metabolomics.Metabolites · 2019Article
- CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole.Pharmacogenomics and personalized medicine · 2018Article
- Distribution of Exogenous and Endogenous CYP3A Markers and Related Factors in Healthy Males and Females.The AAPS journal · 2017Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Endogenous metabolites of cytochrome P450 (CYP3A) are useful in predicting drug-drug interactions between in vivo CYP3A inhibitors and inducers for clinical applications of CYP3A substrate drugs. This study aimed to develop predictable markers of the magnitude of hepatic CYP3A induction and inhibition in healthy female subjects using pharmacometabolomics. Twelve female subjects received midazolam during three study phases: 1 mg midazolam (control phase), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). Throughout the study, blood samples were collected 24 h after midazolam administration and urine samples at 12-h intervals during the 24 h before and after midazolam administration for the analysis of endogenous steroid metabolites. A statistical model was generated to predict midazolam clearance using measurements of endogenous metabolites associated with the inhibition and induction of CYP3A. Mean midazolam clearance decreased to ∼20% of control levels during the inhibition phase and increased more than 2-fold during the induction phase. Of the urine and plasma metabolites measured, the 6β-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6β-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6β-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.
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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.