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Drug-Target Interaction

Drug

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PubChem ID:37632
Structure:
Synonyms:
1-(8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,5-a][1,4]benzodiazepin-1-yl)-N,N-dimethylmethanamine
37115-32-5
4H-(1,2,4)Triazolo(4,3-a)(1,4)benzodiazepine-1-methanamine, 8-chloro-N-N-dimethyl-6-phenyl-
8-Chloro-1-((dimethylamino)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzo
8-Chloro-1-((dimethylamino)methyl)-6-phenyl-4H-s-triazolo(4,3-a)(1,4)benzodiazepine
ADINAZOLAM
Adinazolam (USAN/INN)
Adinazolam [USAN:BAN:INN]
Adinazolam [USAN]
Adinazolamum
Adinazolamum [INN-Latin]
C19H18ClN5
CHEBI:251412
D02770
DB00546
Deracyn
LS-174647
PDSP1_000522
PDSP2_000520
U 41,123
U 41123
U-41123
ATC-Codes:

Target

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Uniprot ID:CP2CJ_HUMAN
Synonyms:
(R)-limonene 6-monooxygenase
(S)-limonene 6-monooxygenase
(S)-limonene 7-monooxygenase
CYPIIC17
CYPIIC19
Cytochrome P450 2C19
Mephenytoin 4-hydroxylase
P450-11A
P450-254C
EC-Numbers:1.14.13.48
1.14.13.49
1.14.13.80
Organism:Homo sapiens
Human
PDB IDs:-

Binding Affinities:

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

References:

9600717
Kinetic characterization and identification of the enzymes responsible for the hepatic biotransformation of adinazolam and N-desmethyladinazolam in man.. K Venkatakrishnan; L L von Moltke; S X Duan; J C Fleishaker; R I Shader; D J Greenblatt (1998) The Journal of pharmacy and pharmacology display abstract
The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10-1000 microM. The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lymphoblastoid cells, and by the use of CYP isoform-selective chemical inhibitors. Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, Km, at which the reaction velocities were 50% of the maximum were 92 and 259 microM, respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (Km 498 microM). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (Km 39 microM) and CYP 3A4 (Km 83 microM); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0.15 microM and the inhibition constant, Ki, was < 0.04 microM in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1.96 microM. The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 microM) and sulphaphenazole, alpha-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (Km 220 microM, Hill number A 1.21), CYP 2C19 (Km 187 microM, Hill number A 1.29) and CYP 2C9 (Km 1068 microM). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0.14 microM) and formation of U (IC50 < 0.1 microM) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.