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Drug-Target Interaction

Drug

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PubChem ID:47576
Structure:
Synonyms:
(+-)-cis-1-acetyl-4-(p-((2-(2,4-dichlorophenyl)-2-(imidazol-1- ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine
(+-)-cis-1-Acetyl-4-(p-((2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine
(-)-Ketoconazole
(2S,4R)-ketoconazole
1-acetyl-4-(4-{[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-
1-ACETYL-4-(4-{[(2S,4R)-2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY}PHENYL)PIPERAZINE
1-[4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
65277-42-1
AIDS-112209
AIDS112209
BRN 4303081
CAS-65277-42-1
CHEBI:47518
CORT-001
CPD-4503
D00351
DB01026
DRG-0073
EINECS 265-667-4
Extina
Fungarest
Fungoral
Ketocanazole
Ketoconazol
Ketoconazol [INN-Spanish]
KETOCONAZOLE
Ketoconazole (JAN/USP)
Ketoconazole [USAN:BAN:INN:JAN]
Ketoconazolum
Ketoconazolum [INN-Latin]
Ketoderm
Ketoisdin
Ketozole
KW-1414
Lopac-K-1003
NCGC00015577-01
NCGC00016907-01
NCGC00161836-01
NCGC00161836-02
Nizoral
Nizoral (TN)
Nizoral a-D
NSC 317629
Orifungal M
Panfungol
Piperazine, (-)-1-acetyl-4-[4-[[(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-
piperazine, 1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H- imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-, cis-
Piperazine, 1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-, cis-
R 41400
R-41400
Sebazole
Xolegel
Xolegel (TN)
ATC-Codes:
Side-Effects:
Side-EffectFrequency
abdominal pain0
nausea0
pain0
papilledema0
paresthesia0
pruritus0
swelling0
thrombocytopenia0
erythema0
urticaria0
vomiting0
chills0
photophobia0
pyogenic granuloma0
dry skin0
scalp seborrhea0
eye swelling0
acne0
leukopenia0
keratoconjunctivitis sicca0
alopecia0
anaphylaxis0
hemolytic anemia0
arrhythmia0
dermatitis0
contact dermatitis0
diarrhea0
dizziness0
somnolence0
rash0
fever0
gynecomastia0
headache0
hypersensitivity0
hypertriglyceridemia0
impetigo0
impotence0
allergic reaction0

Target

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Uniprot ID:CP2C8_HUMAN
Synonyms:
CYPIIC8
Cytochrome P450 2C8
P450 form 1
P450 IIC2
P450 MP-12/MP-20
S-mephenytoin 4-hydroxylase
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:1PQ2 2NNH 2NNI 2NNJ 2VN0
Structure:
2VN0

Binding Affinities:

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

References:

11038157
11136296
The xenobiotic inhibitor profile of cytochrome P4502C8.. C E Ong; S Coulter; D J Birkett; C R Bhasker; J O Miners (2000) British journal of clinical pharmacology display abstract
AIMS: To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A). METHODS: CYP2C8 and NADPH-cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8-catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure. RESULTS: At concentrations of the CYP inhibitor 'probes' employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 microM, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent Ki values of 2.5 microM. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82-91% of control activity) of CYP2C8 at concentrations five-fold higher than the known CYP3A Km. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent Ki values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 microM. CONCLUSIONS: Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.
14709627
Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible.. David M Stresser; Marc I Broudy; Thuy Ho; Catherine E Cargill; Andrew P Blanchard; Raman Sharma; Andre A Dandeneau; Joseph J Goodwin; Stephanie D Turner; John C L Erve; Christopher J Patten; Shangara S Dehal; Charles L Crespi (2004) Drug metabolism and disposition: the biological fate of chemicals display abstract
Azamulin [14-O-(5-(2-amino-1,3,4-triazolyl)thioacetyl)-dihydromutilin] is an azole derivative of the pleuromutilin class of antiinfectives. We tested the inhibition potency of azamulin toward 18 cytochromes P450 using human liver microsomes or microsomes from insect cells expressing single isoforms. In a competitive inhibition model, IC(50) values for CYP3A (0.03-0.24 microM) were at least 100-fold lower than all other non-CYP3A enzymes except CYP2J2 ( approximately 50-fold lower). The IC(50) value with heterologously expressed CYP3A4 was 15-fold and 13-fold less than those of CYP3A5 and CYP3A7, respectively. The reference inhibitor ketoconazole was less selective and exhibited potent inhibition (IC(50) values 300 microM. Azamulin represents an important new chemical tool for use in characterizing the contribution of CYP3A to the metabolism of xenobiotics.
15601807