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Drug-Target Interaction

Drug

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PubChem ID:21319
Structure:
Synonyms:
(2S,5R,6R)-6-({[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
(2S,5R,6R)-6-({[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
(2S,5R,6R)-6-[[3-(2-chloro-6-fluorophenyl)-5-methyl1,2-oxazole-4-carbonyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
3-(2-Chloro-6-fluorophenyl)-5-methyl-4-isoxazolylpenicillin
4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid,
4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 6-(((3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl)carbonyl)amino)-3,3-dimethyl-7-oxo-, (2S(2alpha,5alpha,6beta))
4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[[[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amino]-3,3-dimethyl-7-oxo-, (2S,6R)-
5250-39-5
6-(3-(2-Chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarboxamido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid
6beta-[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole-4-carboxamido]-2,2-dimethylpenam-3alpha-carboxylic acid
BRL 2039
C11748
C19H17ClFN3O5S
CHEBI:5098
D04196
DB00301
EINECS 226-051-0
Floxacillin
Floxacillin (USAN)
Floxacillin [USAN]
Floxapen
Floxapen (TN)
flucloxacilina
Flucloxacilina [INN-Spanish]
Flucloxacillin
Flucloxacillin (INN)
Flucloxacillin Sodium
Flucloxacillin-Sodium
Flucloxacilline
Flucloxacilline [INN-French]
Flucloxacillinum
Flucloxacillinum [INN-Latin]
Fluorochloroxacillin
LS-175377
NCI60_002254
rel-(2R,6S)-6-({[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylato
ATC-Codes:

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:

16472102
Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin.. Jrg Huwyler; Matthew B Wright; Heike Gutmann; Juergen Drewe (2006) Current drug metabolism display abstract
Clinical findings indicate that co-administration of the isoxazolyl-penicillin flucloxacillin with cyclosporine may reduce the plasma concentrations of cyclosporine. We have explored in the present study if induction of cytochrome P450 3A4 or P-glycoprotein may offer a mechanistic explanation of the observed effects. Flucloxacillin is neither an inhibitor nor a substrate of drug metabolizing cytochrome P450 isoenzymes (CYP3A4, 1A2, 2C9, 2C19 and 2D6) or P-glycoprotein as shown by an in vitro assay for CYP inhibition, a fluorescent indicator assay for P-glycoprotein inhibition and a functional P-glycoprotein ATPase assay. However, incubation of human LS 180 colorectal adenocarcinoma cells with flucloxacillin led to a dose-dependent induction of MDR1 as well as of CYP3A4 mRNA, which was also confirmed in primary human hepatocytes. At high concentrations, flucloxacillin activated the human Pregnane-X-Receptor, PXR, a ligand-dependent transcription factor that is the target of many drugs that induce CYP3A4, with consequences for the metabolism of other drugs. Liver microsomes from control rats or rats, which received for 3 consecutive days 100 mg/kg of oral flucloxacillin, were used to study the metabolism and metabolite pattern of midazolam, a model substrate of CYP 3A4. There was a trend towards a higher intrinsic microsomal clearance of midazolam using microsomes from flucloxacillin treated rats. In addition, there was a significant increase in the formation of the principal midazolam metabolites 1-hydroxy midazolam, 4-hydroxy midazolam and 1,4-dihydroxy midazolam as compared to controls. These findings indicate that flucloxacillin has the potential to induce expression of both CYP3A4 as well as P-glycoprotein, most likely through activation of the nuclear hormone receptor PXR. This would offer an explanation for the observed clinical drug-drug interactions between the antibiotic and cyclosporine.