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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11160/17:10374971 RIV/00098892:_____/17:N0000037

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/GA13-01809S" target="_blank" >GA13-01809S: Enantiospecifické interakce mezi klinicky užívanými chirálními léčivy a regulačními drahami humánních cytochromů P450.</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecules

ISSN

1420-3049

e-ISSN

—

Svazek periodika

22

Číslo periodika v rámci svazku

1879

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

14

Strana od-do

1-14

Kód UT WoS článku

000416528400080

EID výsledku v databázi Scopus

2-s2.0-85032461912