ArticleBiochemistry2021
Midazolam as a Probe for Drug-Drug Interactions Mediated by CYP3A4: Homotropic Allosteric Mechanism of Site-Specific Hydroxylation.
Article in Biochemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- The Influence of CBD and THC on Hepatic Enzymes of the Human Cytochrome P450 Complex Family: A Systematic Literature Review.European journal of drug metabolism and pharmacokinetics · 2026Pooled it
- A CYP3A7 metabolically competent human induced pluripotent stem cell-derived hepatocyte-like cell (hHLCDrug metabolism and disposition: the biological fate of chemicals · 2026Article
- Lipid Dependence of CYP3A4 Activity in Nanodiscs.Biology · 2026Article
- Structure-activity relationship studies on 2-thienylidene substituted 3-oxo-2,3-dihydrobenzofuran-7-carboxamides as poly (ADP-ribose) polymerase inhibitors.Bioorganic chemistry · 2025Article
- Drug-drug interaction profile of ritlecitinib as perpetrator and victim through cytochrome P450.British journal of clinical pharmacology · 2025Article
- Quantifying expression and metabolic activity of genes regulated by pregnane X receptor in primary human hepatocyte spheroids.PLoS computational biology · 2025Article
- Precision medication based on the evaluation of drug metabolizing enzyme and transporter functions.Precision clinical medicine · 2025Review
- Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors.Cancer chemotherapy and pharmacology · 2024Article
- Pharmacokinetics study of atracurium, dexmedetomidine, midazolam and 1-hydroxymidazolam in patients undergoing acute aortic dissection surgery.Frontiers in pharmacology · 2024Article
- Review
- A comprehensive evaluation in clinic and physiologically-based pharmacokinetic modeling and simulation to confirm lack of cytochrome P450-mediated drug-drug interaction potential for pomotrelvir.CPT: pharmacometrics & systems pharmacology · 2023Article
- LaGAT: link-aware graph attention network for drug-drug interaction prediction.Bioinformatics (Oxford, England) · 2022Article
- Computer Simulation of the Interaction between SARS-CoV-2 Spike Protein and the Surface of Coinage Metals.Langmuir : the ACS journal of surfaces and colloids · 2022Article
- Article
- Article
- Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 2. Modeling of Experimental Data.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
We developed an efficient and sensitive probe for drug-drug interactions mediated by human CYP3A4 by using midazolam (MDZ) as a probe substrate. Using global analysis of four parameters over several experimental data sets, we demonstrate that the first MDZ molecule (MDZ1) binds with high affinity at the productive site near the heme iron and gives only hydroxylation at the 1 position (1OH). The second midazolam molecule (MDZ2) binds at an allosteric site at the membrane surface and perturbs the position and mobility of MDZ1 such that the minor hydroxylation product at the 4 position (4OH) is formed in a 1:2 ratio (35%). No increase in catalytic rate is observed after the second MDZ binding. Hence, the site of the 1OH:4OH metabolism ratio is a sensitive probe for drugs, such as progesterone, that bind with high affinity to the allosteric site and serve as effectors. We observe similar changes in the MDZ 1OH:4OH ratio in the presence of progesterone (PGS), suggesting a direct communication between the active and allosteric sites. Mutations introduced into the F-F' loop indicate that residues F213 and D214 are directly involved in allosteric interactions leading to MDZ homotropic cooperativity, and these same residues, together with L211, are involved in heterotropic allosteric interactions in which PGS is the effector and MDZ the substrate. Molecular dynamics simulations provide a mechanistic picture of the origin of this cooperativity. These results show that the midazolam can be used as a sensitive probe for drug-drug interactions in human P450 CYP3A4.
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Registered trials
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