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Drug-Target Interaction

Drug

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PubChem ID:5556
Structure:
Synonyms:
28911-01-5
4H-(1,2,4)Triazolo(4,3-a)(1,4)benzodiazepine,
4H-(1,2,4)Triazolo(4,3-a)(1,4)benzodiazepine, 8-chloro-6-(2-chlorophenyl)-1-methyl-
4H-s-Triazolo(4,3-a)(1,4)benzodiazepine, 8-chloro-6-(o-chlorophenyl)-1-methyl-
4H-[1,2,4]Triazolo[4,3-a][1,4]benzodiazepine, 8-chloro-6-(2-chlorophenyl)-1-methyl-
8-Chloro-6-(2-chlorophenyl)-1-methyl-4H-(1,2,4)triazolo(4,3-a)(1,4)benzodiazepine
8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
8-Chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine
8-Chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
8-Chloro-6-[2-chlorophenyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Apo Triazo
Apo-Triazo
Apotex Brand of Triazolam
BRN 1226643
C17H12Cl2N4
CCRIS 1932
CHEBI:9674
Clorazolam
D00387
D014229
DB00897
DEA No. 2887
EINECS 249-307-3
Gen Triazolam
Gen-Triazolam
Genpharm Brand of Triazolam
Gerard Brand of Triazolam
Greenstone Brand of Triazolam
Halcion
Halcion (TN)
Halcion (triazolam)
HSDB 6759
Hypnostat
LS-156323
NCGC00168258-01
nchembio747-comp15
Novidorm
Par Brand of Triazolam
Pharmacia Brand of Triazolam
Pharmacia Spain Brand of Triazolam
Roxane Brand of Triazolam
Schein Brand of Triazolam
Songar
T9772_SIGMA
TGAR01H
TRIAZOLAM
Triazolam (JAN/USP/INN)
Triazolam Greenstone Brand
Triazolam Par Brand
Triazolam Roxane Brand
Triazolam Schein Brand
Triazolam UDL Brand
Triazolam [USAN:BAN:INN:JAN]
Triazolamum [INN-Latin]
Trilam
U 33,030
U 33030
U-33,030
U-33030
U33,030
UDL Brand of Triazolam
ZINC00002212
ATC-Codes:
Side-Effects:
Side-EffectFrequency
dysesthesia0
syncope0
stomatitis0
somnambulism0
pruritus0
paresthesia0
weakness0
pain0
nightmares0
nervousness0
tachycardia0
tinnitus0
anterograde amnesia0
memory impairment0
thinking abnormal0
agitation0
hepatic failure0
urinary retention0
dry mouth0
vomiting0
urinary incontinence0
nausea0
muscle cramps0
jaundice0
dermatitis0
depersonalization0
delusions0
constipation0
confusion0
chest pain0
ataxia0
anxiety0
anorexia0
diarrhea0
dizziness0
irritability0
hypersensitivity0
headache0
hallucinations0
glossitis0
fatigue0
euphoria0
dysarthria0
somnolence0
amnesia0

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:

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.
12814972
In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5.. Kiran C Patki; Lisa L Von Moltke; David J Greenblatt (2003) Drug metabolism and disposition: the biological fate of chemicals display abstract
Midazolam, triazolam (TRZ), testosterone, and nifedipine have all been widely used as probes for in vitro metabolism of CYP3A. We used these four substrates to assess the contributions of CYP3A4 and CYP3A5 to in vitro biotransformation in human liver microsomes (HLMs) and in recombinant enzymes. Recombinant CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) both produced 1-OH and 4-OH metabolites from midazolam and triazolam, 6 beta-hydroxytestosterone from testosterone, and oxidized nifedipine from nifedipine. Overall, the metabolic activity of CYP3A5 was less than that of CYP3A4. Ketoconazole potently inhibited midazolam, triazolam, testosterone, and nifedipine metabolite formation in HLMs and in rCYP3A4. The inhibitory potency of ketoconazole in rCYP3A5 was about 5- to 19-fold less than rCYP3A4 for all four substrates. In testosterone interaction studies, testosterone inhibited 1-OH-TRZ formation, but significantly activated 4-OH-TRZ formation in HLMs and rCYP3A4 but not in rCYP3A5. Oxidized nifedipine formation was inhibited by testosterone in rCYP3A4. However, in rCYP3A5, testosterone slightly activated oxidized nifedipine formation at lower concentrations, followed by inhibition. Thus, CYP3A4 and CYP3A5 both contribute to midazolam, triazolam, testosterone, and nifedipine biotransformation in HLMs, with CYP3A5 being metabolically less active than CYP3A4 in general. Because the inhibitory potency of ketoconazole in rCYP3A5 is substantially less than in rCYP3A4 and HLMs, CYP3A5 is probably less important than CYP3A4 in drug-drug interactions involving ketoconazole and CYP3A substrates.