Influence of Amlodipine Enantiomers on Human Microsomal Cytochromes P450: Stereoselective Time-Dependent Inhibition of CYP3A Enzyme Activity

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F17%3A73582051" target="_blank" >RIV/61989592:15110/17:73582051 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11160/17:10374971 RIV/00098892:_____/17:N0000037
Result on the web
<a href="http://dx.doi.org/10.3390/molecules22111879" target="_blank" >http://dx.doi.org/10.3390/molecules22111879</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/molecules22111879" target="_blank" >10.3390/molecules22111879</a>

Result language
angličtina
Original language name
Influence of Amlodipine Enantiomers on Human Microsomal Cytochromes P450: Stereoselective Time-Dependent Inhibition of CYP3A Enzyme Activity
Original language description
Amlodipine (AML) is available as a racemate, i.e., a mixture of R- and S-enantiomers. Its inhibitory potency towards nine cytochromes P450 (CYP) was studied to evaluate the drug–drug interactions between the enantiomers. Enzyme inhibition was evaluated using specific CYP substrates in human liver microsomes. With CYP3A, both enantiomers exhibited reversible and time-dependent inhibition. S-AML was a stronger reversible inhibitor of midazolam hydroxylation:the Ki values of S- and R-AML were 8.95 microM, 14.85 microM, respectively. Computational docking confirmed that the enantiomers interact differently with CYP3A: the binding free energy of S-AML in the active site was greater than that for R-AML. Conversely, R-AML exhibited more potent time-dependent inhibition of CYP3A activity than S-AML. R-AML was also a significantly more potent inhibitor of CYP2C9 and CYP2C19. In conclusion, results indicate that clinical use of S-AML has an advantage not only because of greater pharmacological effect, but also because of fewer side effects and drug–drug interactions with cytochrome P450 substrates due to absence of R-AML.
Czech name
—
Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30104 - Pharmacology and pharmacy

Project
<a href="/en/project/GA13-01809S" target="_blank" >GA13-01809S: Enantiospecific interactions between clinically used chiral drugs and regulatory pathways of human cytochromes P450.</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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