ArticleClinical pharmacology and therapeutics2012
Evidence of CYP3A allosterism in vivo: analysis of interaction between fluconazole and midazolam.
Article in Clinical pharmacology and therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
19 citing papers in PubMed, 44 citations in OpenAlex.
- Quantitative Prediction of CYP3A4- and CYP3A5-Mediated Drug Interactions.Clinical pharmacology and therapeutics · 2020Trial
- Lipid Dependence of CYP3A4 Activity in Nanodiscs.Biology · 2026Article
- Article
- Midazolam as a Probe for Drug-Drug Interactions Mediated by CYP3A4: Homotropic Allosteric Mechanism of Site-Specific Hydroxylation.Biochemistry · 2021Article
- Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies.Journal of chemical information and modeling · 2021Article
- Numerical Methods for Modeling Enzyme Kinetics.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Modulation of Major Human Liver Microsomal Cytochromes P450 by Component Alkaloids of Goldenseal: Time-Dependent Inhibition and Allosteric Effects.Drug metabolism and disposition: the biological fate of chemicals · 2020Article
- Conformational selection is present in ligand binding to cytochrome P450 19A1 lipoprotein nanodiscs.Journal of inorganic biochemistry · 2020Article
- Dynamics and Location of the Allosteric Midazolam Site in Cytochrome P4503A4 in Lipid Nanodiscs.Biochemistry · 2020Article
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
- An LC-MS/MS Bioanalytical Assay for the Determination of Gilteritinib in Rat Plasma and Application to a Drug-Drug Interaction Study.Drug design, development and therapy · 2020Article
- Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism.Archives of biochemistry and biophysics · 2019Review
- Membrane-embedded substrate recognition by cytochrome P450 3A4.The Journal of biological chemistry · 2018Article
- A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer.Biochemistry · 2015Article
- Heterotropic activation of the midazolam hydroxylase activity of CYP3A by a positive allosteric modulator of mGlu5: in vitro to in vivo translation and potential impact on clinically relevant drug-drug interactions.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Should Midazolam Drug-Drug Interactions be of Concern to Palliative Care Physicians?Drug safety · 2013Article
- Effect of CYP3A5 expression on the inhibition of CYP3A-catalyzed drug metabolism: impact on modeling CYP3A-mediated drug-drug interactions.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- A novel type of allosteric regulation: functional cooperativity in monomeric proteins.Archives of biochemistry and biophysics · 2012Review
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5 authors at 2 institutions in 1 country.
Funding
Abstract
The allosteric effect of fluconazole (effector) on the formation of 1'-hydroxymidazolam (1'-OH-MDZ) and 4-hydroxymidazolam (4-OH-MDZ) from midazolam (MDZ), a substrate of CYP3A4/5--members of the cytochrome P450 superfamily of enzymes--was examined in healthy volunteers. Following pretreatment with fluconazole, the ratio of the areas under the curve (AUCs) for 4-OH-MDZ and MDZ (AUC(4-OH)/AUC(MDZ)) increased by 35-62%, whereas the ratio AUC(1'-OH)/AUC(MDZ) decreased by 5-37%; the ratio AUC(1'-OH)/AUC(4-OH) decreased by 46-58% after fluconazole administration and had no association with the CYP3A5 genotype. The in vitro formation of 1'-OH-MDZ was more susceptible to inhibition by fluconazole than that of 4-OH-MDZ. Fluconazole decreased the intrinsic formation-clearance ratio of 1'-OH-MDZ/4-OH-MDZ to an extent that was quantitatively comparable to in vivo observations. The elimination clearance of MDZ metabolites appeared unaffected by fluconazole. This study demonstrated that fluconazole alters formation of MDZ metabolites, both in vivo and in vitro, in a manner consistent with an allosteric interaction. The 1'-OH-MDZ/4-OH-MDZ ratio may serve as a biomarker of such interactions among MDZ, CYP3A4/5, and other putative effectors.
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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.