In vitro analysis of itraconazole cis-diastereoisomers inhibition of nine cytochrome P450 enzymes: stereoselective inhibition of CYP3A

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F19%3A73594657" target="_blank" >RIV/61989592:15110/19:73594657 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/19:73594657

Výsledek na webu

<a href="https://www.tandfonline.com/doi/abs/10.1080/00498254.2018.1425510" target="_blank" >https://www.tandfonline.com/doi/abs/10.1080/00498254.2018.1425510</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1080/00498254.2018.1425510" target="_blank" >10.1080/00498254.2018.1425510</a>

Jazyk výsledku

angličtina

Název v původním jazyce

In vitro analysis of itraconazole cis-diastereoisomers inhibition of nine cytochrome P450 enzymes: stereoselective inhibition of CYP3A

Popis výsledku v původním jazyce

1.Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2 &apos; R-ITZ-A; (+)-2R,4S,2 &apos; S-ITZ-B; (-)-2S,4R,2 &apos; S-ITZ-C and (-)-2S,4R,2 &apos; R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. 2.As ITZ is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated. 3.All ITZ diastereoisomers dose-dependently inhibited CYP3A activity in both used assays, midazolam and testosterone hydroxylation. The K-i values were assessed: for testosterone ITZ-A/0.085 mu M; ITZ-B/0.91 mu M, ITZ-C/0.20 mu M and ITZ-D/0.022 mu M; for midazolam ITZ-A/0.44 mu M; ITZ-B/0.48 mu M, ITZ-C/1.56 mu M and ITZ-D/3.48 mu M. The enzyme activity of CYP2C19 was moderately inhibited (IC50 30-53 mu M), but in this case without large differences between the individual optical isomers. 4.The significant differences between diastereoisomers were presented. Antifungal potency of ITZ stereoisomers also differs so the potential enantiopure preparations of ITZ was not of interest.

Název v anglickém jazyce

In vitro analysis of itraconazole cis-diastereoisomers inhibition of nine cytochrome P450 enzymes: stereoselective inhibition of CYP3A

Popis výsledku anglicky

1.Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2 &apos; R-ITZ-A; (+)-2R,4S,2 &apos; S-ITZ-B; (-)-2S,4R,2 &apos; S-ITZ-C and (-)-2S,4R,2 &apos; R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. 2.As ITZ is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated. 3.All ITZ diastereoisomers dose-dependently inhibited CYP3A activity in both used assays, midazolam and testosterone hydroxylation. The K-i values were assessed: for testosterone ITZ-A/0.085 mu M; ITZ-B/0.91 mu M, ITZ-C/0.20 mu M and ITZ-D/0.022 mu M; for midazolam ITZ-A/0.44 mu M; ITZ-B/0.48 mu M, ITZ-C/1.56 mu M and ITZ-D/3.48 mu M. The enzyme activity of CYP2C19 was moderately inhibited (IC50 30-53 mu M), but in this case without large differences between the individual optical isomers. 4.The significant differences between diastereoisomers were presented. Antifungal potency of ITZ stereoisomers also differs so the potential enantiopure preparations of ITZ was not of interest.

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

2019

Kód důvěrnosti údajů

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

Název periodika

XENOBIOTICA

ISSN

0049-8254

e-ISSN

—

Svazek periodika

49

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

7

Strana od-do

36-42

Kód UT WoS článku

000457019900004

EID výsledku v databázi Scopus

2-s2.0-85041116164