Cargando…

Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4

Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-me...

Descripción completa

Detalles Bibliográficos
Autores principales: Denisov, Ilia G., Grinkova, Yelena V., McLean, Mark A., Camp, Tyler, Sligar, Stephen G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221276/
https://www.ncbi.nlm.nih.gov/pubmed/35740978
http://dx.doi.org/10.3390/biom12060853
_version_ 1784732581149802496
author Denisov, Ilia G.
Grinkova, Yelena V.
McLean, Mark A.
Camp, Tyler
Sligar, Stephen G.
author_facet Denisov, Ilia G.
Grinkova, Yelena V.
McLean, Mark A.
Camp, Tyler
Sligar, Stephen G.
author_sort Denisov, Ilia G.
collection PubMed
description Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-mediated DDI, we evaluated the application of midazolam (MDZ) as a probe substrate. MDZ is hydroxylated by CYP3A4 in two positions: 1-hydroxy MDZ formed at lower substrate concentrations, and up to 35% of 4-hydroxy MDZ at high concentrations. The ratio of the formation rates of these two products (the site of metabolism ratio, SOM) was used as a measure of allosteric heterotropic interactions caused by effector molecules using CYP3A4 incorporated in lipid nanodiscs. The extent of the changes in the SOM in the presence of effectors is determined by chemical structure and is concentration-dependent. MD simulations of CYP3A4 in the lipid bilayer suggest that experimental results can be explained by the movement of the F-F’ loop and concomitant changes in the shape and volume of the substrate-binding pocket. As a result of PGS binding at the allosteric site, several residues directly contacting MDZ move away from the substrate molecule, enabling the repositioning of the latter for minor product formation.
format Online
Article
Text
id pubmed-9221276
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-92212762022-06-24 Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4 Denisov, Ilia G. Grinkova, Yelena V. McLean, Mark A. Camp, Tyler Sligar, Stephen G. Biomolecules Article Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-mediated DDI, we evaluated the application of midazolam (MDZ) as a probe substrate. MDZ is hydroxylated by CYP3A4 in two positions: 1-hydroxy MDZ formed at lower substrate concentrations, and up to 35% of 4-hydroxy MDZ at high concentrations. The ratio of the formation rates of these two products (the site of metabolism ratio, SOM) was used as a measure of allosteric heterotropic interactions caused by effector molecules using CYP3A4 incorporated in lipid nanodiscs. The extent of the changes in the SOM in the presence of effectors is determined by chemical structure and is concentration-dependent. MD simulations of CYP3A4 in the lipid bilayer suggest that experimental results can be explained by the movement of the F-F’ loop and concomitant changes in the shape and volume of the substrate-binding pocket. As a result of PGS binding at the allosteric site, several residues directly contacting MDZ move away from the substrate molecule, enabling the repositioning of the latter for minor product formation. MDPI 2022-06-20 /pmc/articles/PMC9221276/ /pubmed/35740978 http://dx.doi.org/10.3390/biom12060853 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Denisov, Ilia G.
Grinkova, Yelena V.
McLean, Mark A.
Camp, Tyler
Sligar, Stephen G.
Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title_full Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title_fullStr Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title_full_unstemmed Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title_short Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4
title_sort midazolam as a probe for heterotropic drug-drug interactions mediated by cyp3a4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221276/
https://www.ncbi.nlm.nih.gov/pubmed/35740978
http://dx.doi.org/10.3390/biom12060853
work_keys_str_mv AT denisoviliag midazolamasaprobeforheterotropicdrugdruginteractionsmediatedbycyp3a4
AT grinkovayelenav midazolamasaprobeforheterotropicdrugdruginteractionsmediatedbycyp3a4
AT mcleanmarka midazolamasaprobeforheterotropicdrugdruginteractionsmediatedbycyp3a4
AT camptyler midazolamasaprobeforheterotropicdrugdruginteractionsmediatedbycyp3a4
AT sligarstepheng midazolamasaprobeforheterotropicdrugdruginteractionsmediatedbycyp3a4