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Drug-Target Interaction

Drug

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PubChem ID:2477
Structure:
Synonyms:
36505-84-7
5-25-10-00059 (Beilstein Handbook Reference)
8-(4-(4-(2-Pyrimidinyl)-1-piperizinyl)butyl)-8-azaspiro(4,5)decane-7,9-dione
8-Azaspiro(4,5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)piperizinyl)butyl)-
8-Azaspiro(4.5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-
8-Azaspiro[4.5]decane-7,9-dione, 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-
8-[4-(4-Pyrimidin-2-yl-piperazin-1-yl)-butyl]-8-aza-spiro[4.5]decane-7,9-dione
8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dion
8-[4-(4-pyrimidin-2-ylpiperazin-1-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione
AB00053432
Ansial
BAS 00928841
Biomol-NT_000108
BPBio1_000547
BPBio1_001403
BRN 0964904
BSPBio_000497
Buspar
Buspirona
Buspirona [INN-Spanish]
Buspirone
Buspirone (INN)
Buspirone HCL
Buspirone hydrochloride
Buspirone [INN:BAN]
Buspirone-MDTS
Buspironum
Buspironum [INN-Latin]
C06861
C13H21NO2.C9H14N4
CAS-33386-08-2
CHEBI:3223
CID2477
D07593
DB00490
DivK1c_000921
EINECS 253-072-2
Gen-Buspirone
Gen-Buspirone (TN)
IDI1_000921
KBio1_000921
KBio2_002236
KBio2_004804
KBio2_007372
KBioSS_002236
Lopac-B-7148
Lopac0_000223
LS-22723
MJ-9022-1
N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1-cyclopentanediacetamide
NCGC00015162-01
NCGC00016820-01
NCGC00024905-01
NCGC00024905-02
NCGC00024905-03
NINDS_000921
Prestwick0_000369
Prestwick1_000369
Prestwick2_000369
Prestwick3_000369
SPBio_002418
Spectrum_001756
STOCK1S-11244
Tocris-0962
ATC-Codes:
Side-Effects:
Side-EffectFrequency
insomnia1.0
paresthesia1.0
weakness1.0
numbness1.0
nightmares1.0
nervousness1.0
nausea1.0
nasal congestion1.0
fatigue1.0
sweating1.0
tachycardia1.0
blurred vision1.0
sore throat1.0
muscle aches1.0
lightheadedness1.0
dry mouth1.0
vomiting1.0
tremor1.0
tinnitus1.0
skin rash1.0
chest pain1.0
headache1.0
drowsiness1.0
constipation1.0
diarrhea1.0
confusion1.0
dizziness0.667
anorexia0.01
weight loss0.01
chills0.01
hypersalivation0.01
spasms0.01
arthralgia0.01
malaise0.01
menstrual irregularity0.01
dry skin0.01
blisters0.01
rectal bleeding0.01
shortness of breath0.01
hypertension0.01
hypotension0.01
weight gain0.01
fever0.01
flatulence0.01
urinary frequency0.01
irritable colon0.01
hair loss0.01
easy bruising0.01
breakthrough bleeding0.01
flushing0.01
muscle cramps0.01
edema0.009999999
pruritus0.009999999
seizures0.0082
hallucinations0.0082
syncope0.0082
alcohol abuse0.0010
photophobia0.0010
restlessness0.0010
amenorrhea0.0010
cerebrovascular accident0.0010
cardiomyopathy0.0010
acne0.0010
parkinsonism0.0010
allergic reactions0.0010
galactorrhea0.0010
bradycardia0.0010
angioedema0.0010
stiff neck0.0010
urinary retention0.0010
enuresis0.0010
myocardial infarction0.0010
serotonin syndrome0.0010
leukopenia0.0010
flu0.0010
hiccups0.0010
congestive heart failure0.0010
eosinophilia0.0010
epistaxis0.0010
ecchymosis0.0010
dyskinesias0.0010
nocturia0.0010
ataxias0.0010
impotence0.0010
vertigo0.0010
urticaria0.0010
erythema0.0010
cold intolerance0.0010
thrombocytopenia0.0010
restless leg syndrome0.0010
psychosis0.0010
thinking abnormal0
excitement0
feeling high0
depersonalization0
emotional lability0
euphoria0
dysphoria0
stupor0
hemorrhage0
palpitations0
urinary hesitancy0
pelvic inflammatory disease0
dysuria0
conjunctivitis0
aphonia0
eye pain0
muscle weakness0
anger0

Target

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Uniprot ID:CP3A4_HUMAN
Synonyms:
Albendazole monooxygenase
Albendazole sulfoxidase
CYPIIIA3
CYPIIIA4
Cytochrome P450 3A3
Cytochrome P450 3A4
HLp
NF-25
Nifedipine oxidase
P450-PCN1
Quinine 3-monooxygenase
Taurochenodeoxycholate 6-alpha-hydroxylase
EC-Numbers:1.14.13.32
1.14.13.67
1.14.13.97
Organism:Homo sapiens
Human
PDB IDs:1TQN 1W0E 1W0F 1W0G 2J0D 2V0M
Structure:
2V0M

Binding Affinities:

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

References:

010227067
11095581
Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates.. D M Stresser; A P Blanchard; S D Turner; J C Erve; A A Dandeneau; V P Miller; C L Crespi (2000) Drug metabolism and disposition: the biological fate of chemicals display abstract
Inhibition of cytochrome P450 catalytic activity is a principal mechanism for pharmacokinetic drug-drug interactions. Rapid, in vitro testing for cytochrome P450 inhibition potential is part of the current paradigm for identifying drug candidates likely to give such interactions. We have explored the extent that qualitative and quantitative inhibition parameters are dependent on the cytochrome P450 (CYP) 3A4 probe substrate. Inhibition potential (e.g., IC(50) values from 8-point inhibition curves) or activation potential for most compounds varied dramatically depending on the fluorometric probe substrates for CYP3A4 [benzyloxyresorufin (BzRes), 7-benzyloxy-4-trifluoromethylcoumarin (BFC), 7-benzyloxyquinoline (BQ), and dibenzylfluorescein (DBF)]. For 21 compounds that were primarily inhibitors, the range of IC(50) values for the four substrates varied from 2.1- to 195-fold with an average of 29-fold. While the rank order of sensitivity among the fluorometric substrates varied among the individual inhibitors, on average, BFC dealkylation was the most sensitive to inhibition, while BQ dealkylation was least sensitive. Partial inhibition was observed with BzRes and BQ but not for BFC and DBF. BzRes was more prone to activation, whereas dramatic changes in IC(50) values were observed when the BQ concentration was below the S(50). Three different correlation analyses indicated that IC(50) values with BFC, BQ, and DBF correlated well with each other, whereas the response with BzRes correlated more weakly with the other substrates. One of these correlation analyses was extended to the percent inhibition of 10 microM inhibitor with the standard CYP3A4 probe substrates testosterone, midazolam, and nifedipine. In this analysis the responses with BQ, BFC and DBF correlated well with testosterone and midazolam but more poorly with nifedipine. In the aggregate, BFC and DBF appear more suitable as an initial screen for CYP3A4 inhibition. However, the substrate-dependent effects reported here and by others indicate that all CYP3A4 inhibition data should be interpreted with caution.
12549947
14566442
15640381
Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes.. Mingshe Zhu; Weiping Zhao; Humberto Jimenez; Donglu Zhang; Suresh Yeola; Renke Dai; Nimish Vachharajani; James Mitroka (2005) Drug metabolism and disposition: the biological fate of chemicals display abstract
This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3'-hydroxybuspirone (3'-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6'-hydroxybuspirone (6'-OH-Bu) in HLMs. The apparent K(m) values for buspirone metabolite formation in pooled HLMs were 8.7 (1-PP), 34.0 (Bu N-oxide), 4.3 (3'-OH-Bu), 11.4/514 (5-OH-Bu), and 8.8 microM (6'-OH-Bu). CYP3A inhibitor ketoconazole (1 microM) completely inhibited the formation of all major metabolites in HLMs (0-16% of control), whereas the chemical inhibitor selective to other P450 isoforms had little or no inhibitory effect. Recombinant CYP3A4, CYP3A5, and CYP2D6 exhibited buspirone oxidation activities among nine P450 isoforms tested. The overall metabolism rate of 5 microM buspirone by CYP3A4 was 18-fold greater than that by CYP2D6 and 35-fold greater than that by CYP3A5. In a panel of HLMs from 16 donors, buspirone metabolism correlated well CYP3A activity (r2 = 0.85-0.96, rho < 0.0005), but not the activities of other P450 isoforms. The metabolism rates of buspirone in CYP2D6 poor-metabolizer genotype HLMs were comparable to those in pooled HLMs. Taken together, these data suggest that CYP3A, mostly likely CYP3A4, is primarily responsible for the metabolism of buspirone in HLMs.
17376576
9333111
Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.. K T Kivist÷; T S Lamberg; T Kantola; P J Neuvonen (1997) Clinical pharmacology and therapeutics display abstract
BACKGROUND: The oral bioavailability of buspirone is very low as a result of extensive first-pass metabolism. Erythromycin and itraconazole are potent inhibitors of CYP3A4, and they increase plasma concentrations and effects of certain drugs, for example, oral midazolam and triazolam. The possible interactions of buspirone with erythromycin and itraconazole have not been studied before. METHODS: The pharmacokinetics and pharmacodynamics of buspirone were investigated in a randomized, double-blind, double-dummy crossover study with three phases. Eight young healthy volunteers took either 1.5 gm/day erythromycin, 200 mg/day itraconazole, or placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. Timed blood samples were collected up to 18 hours, and the effects of buspirone were measured with four psychomotor tests up to 8 hours. RESULTS: Erythromycin and itraconazole increased the mean area under the plasma concentration-time curve from time zero to infinity [AUC(0-infinity] of buspirone about sixfold (p < 0.05) and 19-fold (p < 0.01), respectively, compared with placebo. The mean peak plasma concentration (Cmax) of buspirone was increased about fivefold (p < 0.01) and 13-fold (p < 0.01) by erythromycin and itraconazole, respectively. These interactions were evident in each subject, although a striking interindividual variability in the extent of both interactions was observed. The elimination half-life of buspirone did not seem to be prolonged by either erythromycin or itraconazole. The effect of itraconazole on the Cmax and AUC(0-infinity) of buspirone was significantly (p < 0.01) greater than that of erythromycin. The greatly elevated plasma buspirone concentrations resulted in increased (p < 0.05) pharmacodynamic effects (as measured by the Digit Symbol Substitution test and the Critical Flicker Fusion test) and in side effects of buspirone. CONCLUSIONS: Both erythromycin and itraconazole greatly increased plasma buspirone concentrations, obviously by inhibiting its CYP3A4-mediated first-pass metabolism. These pharmacokinetic interactions were accompanied by impairment of psychomotor performance and side effects of buspirone. The dose of buspirone should be greatly reduced during concomitant treatment with erythromycin, itraconazole, or other potent inhibitors of CYP3A4.
9871430