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Drug-Target Interaction

Drug

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PubChem ID:636806
Structure:
Synonyms:
3,5-pyridinedicarboxylic acid, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-, ethyl methyl ester
4-(2,3-dichloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic
4-(2,3-dichloro-phenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester
72509-76-3
AC1LCSY4
CHEMBL254609
ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Felodipine
Lopac-F-9677
NCGC00015455-01
NCGC00015455-02
ZINC19802035
ATC-Codes:
Side-Effects:
Side-EffectFrequency
sexual dysfunction0.0010
postural hypotension0.0010
hypotension0.0010
salivary gland enlargement0.0010
urinary urgency0.0010
hepatitis0.0010
myalgia0.0010
impotence0.0010
flatulence0.0010
fever0.0010
dry mouth0.0010
vomiting0.0010
flu0.0010
pruritis0.0010
polyuria0.0010
syncope0.0010
tachycardia0.0010
tremor0.0010
nervousness0.0010
myocardial infarction0.0010
muscle cramps0.0010
urticaria0.0010
erythema nodosum0.0010
erythema multiforme0.0010
epistaxis0.0010
confusion0.0010
chest pain0.0010
leucocytoclastic vasculitis0.0010
insomnia0.0010
arthralgia0.0010
arrhythmia0.0010
anxiety0.0010
angioedema0.0010
angina pectoris0.0010
anemia0.0010
abdominal pain0.0010
urinary frequency0.0010
bradycardia0.0010
photosensitivity0.0010
diarrhea0.0010
edema0.0010
somnolence0.0010
dysuria0.0010
dyspnea0.0010
regurgitation0.0010
knee pain0
bronchitis0
peripheral edema0
erythema0
rhinorrhea0
upper respiratory tract infection0
arm pain0
sneezing0
sinusitis0
foot pain0
rash0
dyspepsia0
dizziness0
decreased libido0
cough0
constipation0
back pain0
gynecomastia0
headache0
hip pain0
pharyngitis0
paresthesia0
palpitations0
nausea0
leg pain0
irritability0
infection0
flushing0
asthenia0

Target

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Uniprot ID:CP2D6_HUMAN
Synonyms:
CYPIID6
Cytochrome P450 2D6
Debrisoquine 4-hydroxylase
P450-DB1
EC-Numbers:1.14.14.1
Organism:Homo sapiens
Human
PDB IDs:2F9Q
Structure:
2F9Q

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.
9153299
Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.. K S Lown; D G Bailey; R J Fontana; S K Janardan; C H Adair; L A Fortlage; M B Brown; W Guo; P B Watkins (1997) The Journal of clinical investigation display abstract
The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.