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Drug-Target Interaction

Drug

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PubChem ID:39186
Structure:
Synonyms:
(2S,3S)-5-[2-(dimethylamino)ethyl]-2-[4-(methyloxy)phenyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate
1,5-Benzothiazepin-4(5H)-one,
1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-, (2S-cis)-
1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S,3S)-
144604-00-2 (MALATE)
33286-22-5 (HYDROCHLORIDE)
42399-41-7
Acalix
Adizem
AIDS-000583
AIDS000583
Aldizem
Anoheal
Bio1_000371
Bio1_000860
Bio1_001349
BPBio1_000230
BRN 3573079
BSPBio_000208
BSPBio_001311
C06958
C22H26N2O4S
Cardil
Cardizem
Cardizem (Hydrochloride)
Cardizem LA
CHEBI:101278
CRD-401
d-cis-Diltiazem
DB00343
Dilacor XR
Dilcontin
Dilren
Dilt-cd
Dilta-Hexal
Diltiazem
Diltiazem hydrochloride
Diltiazem [INN:BAN]
Diltiazemum
Diltiazemum [INN-Latin]
Dilticard
Diltzac
Dilzem
Dilzen
EINECS 255-796-4
Endrydil
HSDB 6528
Incoril AP
Lopac0_000327
LS-40510
MK-793 (Malate)
NCGC00024309-02
NCGC00024309-04
NCGC00024309-05
NCGC00024309-06
NCGC00024309-07
NCGC00024309-08
NCGC00024309-09
Prestwick0_000134
Prestwick1_000134
Prestwick2_000134
Prestwick3_000134
RG 83606 (Hydrochloride)
SPBio_002147
STOCK1N-03672
Tiamate
Tiazac XC
Tocris-0685
[(2S,3S)-5-(2-dimethylaminoethyl)-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate
ATC-Codes:

Target

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Uniprot ID:CP2C9_HUMAN
Synonyms:
(R)-limonene 6-monooxygenase
(S)-limonene 6-monooxygenase
(S)-limonene 7-monooxygenase
CYPIIC9
Cytochrome P450 2C9
P-450MP
P450 MP-4/MP-8
P450 PB-1
S-mephenytoin 4-hydroxylase
EC-Numbers:1.14.13.48
1.14.13.49
1.14.13.80
Organism:Homo sapiens
Human
PDB IDs:1OG2 1OG5 1R9O
Structure:
1R9O

Binding Affinities:

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

References:

10640508
Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.. B Ma; T Prueksaritanont; J H Lin (2000) Drug metabolism and disposition: the biological fate of chemicals display abstract
The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 microM, whereas those for all others ranged from 14 to >150 microM. Except for nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone 6beta-hydroxylation and midazolam 1'-hydroxylation) after 30-min preincubation with NADPH. IC(50) values for the inhibition of testosterone 6beta-hydroxylase obtained in the NADPH-preincubation experiment for nicardipine (1 microM), verapamil (2 microM), and diltiazem (5 microM) were within 10-fold, whereas those for amlodipine (5 microM) and felodipine (13 microM) were >200-fold of their respective plasma concentrations reported after therapeutic doses. Similar results also were obtained based on midazolam 1'-hydroxylase activity. Unlike the observations with mibefradil, a potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A activity by nicardipine and verapamil was completely reversible on dialysis, whereas that by diltiazem was partially restored (80%). Additional experiments revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent of complex formation ( approximately 30% at 100 microM), and was a much faster-acting inhibitor (maximal inhibition rate constant approximately 2 min(-1)) as compared with verapamil and diltiazem. These present findings that the CYP3A inhibition caused by nicardipine, verapamil, and diltiazem is, at least in part, quasi-irreversible provide a rational basis for pharmacokinetically significant interactions reported when they were coadministered with agents that are cleared primarily by CYP3A-mediated pathways.
9223567