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Statements

Subject Item
n2:RIV%2F61989592%3A15310%2F11%3A33119053%21RIV12-GA0-15310___
rdf:type
n13:Vysledek skos:Concept
dcterms:description
Azoles antifungals are widespread used drugs for various medicinal indications. These drugs are well known for their numerous drug-drug interactions, which are believed to occur via inhibition of CYP3A4 enzymatic activity and consequently altering pharmacokinetic of co-administered drugs. In the current communication a complex view on the molecular interactions between azoles antimycotics and CYP3A4 is presented. Beside inhibition of CYP3A4 catalytic activity, azoles influence transcriptional activity of pregnane X receptor (PXR) and consequently expression of drug-metabolizing enzymes, including CYP3A4. Interactions between azoles and PXR occur by multiple mechanisms, including modulation of ligand-dependent activation of PXR (agonism, antagonism) or affecting recruitment of PXR co-activators SRC-1 (steroid receptorco-activator 1)and HNF4 alpha (hepatocyte nuclear factor 4 alpha). Miconazole and ketoconazole are antagonists of glucocorticoid receptor (GR), therefore these drugs inhibit GR-mediated expression of PXR and drug metabolizing cytochromes P450. In addition, PXR and GB are key regulators of intermediary metabolism (e.g. carbohydrate, lipids or bile acids homeostasis) and many other cellular functions (e.g. immune response), hence, the interactions between azoles and PXR/GR are of broader physiological importance. In conclusion, while inhibition of CYP3A4 enzymatic activity by azoles is considered as primary cause of azoles drug-drug interactions, the effects of azoles on PXR and GR should be taken in account. Apart from CYP3A4, azoles influence the expression and activity of others drug-metabolizing cytochromes P450. Azoles antifungals are widespread used drugs for various medicinal indications. These drugs are well known for their numerous drug-drug interactions, which are believed to occur via inhibition of CYP3A4 enzymatic activity and consequently altering pharmacokinetic of co-administered drugs. In the current communication a complex view on the molecular interactions between azoles antimycotics and CYP3A4 is presented. Beside inhibition of CYP3A4 catalytic activity, azoles influence transcriptional activity of pregnane X receptor (PXR) and consequently expression of drug-metabolizing enzymes, including CYP3A4. Interactions between azoles and PXR occur by multiple mechanisms, including modulation of ligand-dependent activation of PXR (agonism, antagonism) or affecting recruitment of PXR co-activators SRC-1 (steroid receptorco-activator 1)and HNF4 alpha (hepatocyte nuclear factor 4 alpha). Miconazole and ketoconazole are antagonists of glucocorticoid receptor (GR), therefore these drugs inhibit GR-mediated expression of PXR and drug metabolizing cytochromes P450. In addition, PXR and GB are key regulators of intermediary metabolism (e.g. carbohydrate, lipids or bile acids homeostasis) and many other cellular functions (e.g. immune response), hence, the interactions between azoles and PXR/GR are of broader physiological importance. In conclusion, while inhibition of CYP3A4 enzymatic activity by azoles is considered as primary cause of azoles drug-drug interactions, the effects of azoles on PXR and GR should be taken in account. Apart from CYP3A4, azoles influence the expression and activity of others drug-metabolizing cytochromes P450.
dcterms:title
Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition
skos:prefLabel
Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition
skos:notation
RIV/61989592:15310/11:33119053!RIV12-GA0-15310___
n13:predkladatel
n15:orjk%3A15310
n3:aktivita
n16:P
n3:aktivity
P(GAP304/10/0149), P(GAP503/10/0579)
n3:cisloPeriodika
2
n3:dodaniDat
n9:2012
n3:domaciTvurceVysledku
n14:8069239
n3:druhVysledku
n17:J
n3:duvernostUdaju
n11:S
n3:entitaPredkladatele
n18:predkladatel
n3:idSjednocenehoVysledku
195495
n3:idVysledku
RIV/61989592:15310/11:33119053
n3:jazykVysledku
n19:eng
n3:klicovaSlova
Drug interactions; Glucocorticoid receptor; Pregnane X receptor; Cytochrome CYP3A4; Azoles
n3:klicoveSlovo
n5:Pregnane%20X%20receptor n5:Azoles n5:Drug%20interactions n5:Cytochrome%20CYP3A4 n5:Glucocorticoid%20receptor
n3:kodStatuVydavatele
IE - Irsko
n3:kontrolniKodProRIV
[CDB5836729D2]
n3:nazevZdroje
Toxicology Letters
n3:obor
n4:FR
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
1
n3:projekt
n7:GAP304%2F10%2F0149 n7:GAP503%2F10%2F0579
n3:rokUplatneniVysledku
n9:2011
n3:svazekPeriodika
202
n3:tvurceVysledku
Dvořák, Zdeněk
n3:wos
000289708000007
s:issn
0378-4274
s:numberOfPages
4
n20:doi
10.1016/j.toxlet.2011.01.027
n12:organizacniJednotka
15310