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Drug-Target Interaction

Drug

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PubChem ID:166558
Structure:
Synonyms:
((2,4,6-Tris(1-methylethyl)phenyl)acetyl)sulfamic acid
((2,4,6-Tris(1-methylethyl)phenyl)acetyl)sulfamic acid 2,6-bis(1-methylethyl)phenyl ester
166518-60-1
2,6-bis(1-methylethyl)phenyl ((2,4,6-tris(1-methylethyl)phenyl)acetyl)sulfamate
2,6-Diisopropylphenyl ((2,4,6-triisopropylphenyl)acetyl)sulfamate
2,6-diisopropylphenyl[(2,4,6-triisopropylphenyl)acetyl]sulfamate
Avasimibe
Avasimibe (USAN/INN)
Avasimibe [USAN]
Avasimibe, CI-1011
Benzeneacetamide, N-((2,6-bis(1-methylethyl)phenoxy)sulfonyl)-2,4,6-tris(1-methylethyl)-
C423185
CI 1011
CI-1011
D03012
LS-28486
N-((2,6-Bis(1-methylethyl)phenoxy)sulfonyl)-2,4,6-tris(1-methylethyl)-benzeneacetamide
N-((2,6-Bis(1-methylethyl)phenoxy)sulfonyl)-2,4,6-tris(1-methylethyl)benzeneacetamide

Target

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Uniprot ID:NR1I2_HUMAN
Synonyms:
Nuclear receptor subfamily 1 group I member 2
Orphan nuclear receptor PAR1
Orphan nuclear receptor PXR
Pregnane X receptor
Steroid and xenobiotic receptor
SXR
EC-Numbers:-
Organism:Homo sapiens
Human
PDB IDs:1ILG 1ILH 1M13 1NRL 1SKX 2O9I 2QNV 3CTB 3HVL
Structure:
3HVL

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----

References:

12766253
Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor.. Jasminder Sahi; Mark A Milad; Xianxian Zheng; Kelly A Rose; Hongbing Wang; Linda Stilgenbauer; Darryl Gilbert; Summer Jolley; Ralph H Stern; Edward L LeCluyse (2003) The Journal of pharmacology and experimental therapeutics display abstract
In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC50 of 200-400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 microM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 microM rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC50 values of 20.7, 1.6, and 3.1 microM using testosterone, midazolam, and felodipine as probe substrates, respectively. Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1.