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

Result code in 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>
Alternative codes found
RIV/61989592:15310/19:73594657
Result on the web
<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>

Result language
angličtina
Original language name
In vitro analysis of itraconazole cis-diastereoisomers inhibition of nine cytochrome P450 enzymes: stereoselective inhibition of CYP3A
Original language description
1.Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2 ' R-ITZ-A; (+)-2R,4S,2 ' S-ITZ-B; (-)-2S,4R,2 ' S-ITZ-C and (-)-2S,4R,2 ' 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.
Czech name
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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
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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
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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