ArticleDrug metabolism and disposition: the biological fate of chemicals2013
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.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 23 citations in OpenAlex.
- Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol.Pharmaceutics · 2024Article
- Article
- Complex Cytochrome P450 Kinetics Due to Multisubstrate Binding and Sequential Metabolism. Part 1. Theoretical Considerations.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies.Journal of chemical information and modeling · 2021Article
- Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.Journal of medicinal chemistry · 2020Article
- Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.Liver research (Beijing, China) · 2019Article
- Correction to "Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213".Biochemistry · 2019Article
- Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213.Biochemistry · 2019Article
- 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
- Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia.ACS medicinal chemistry letters · 2015Article
- Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer.Biochemistry · 2015Article
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Authors and funding
17 authors at 2 institutions in 2 countries.
Funding
Abstract
Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu(5) PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V(max) (minimal change in K(m)) and required the presence of cytochrome b5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation.
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