FLUPHENAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H26F3N3OS
Molecular Weight	437.522
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OCCN1CCN(CCCN2C3=C(SC4=C2C=C(C=C4)C(F)(F)F)C=CC=C3)CC1

InChI

InChIKey=PLDUPXSUYLZYBN-UHFFFAOYSA-N

InChI=1S/C22H26F3N3OS/c23-22(24,25)17-6-7-21-19(16-17)28(18-4-1-2-5-20(18)30-21)9-3-8-26-10-12-27(13-11-26)14-15-29/h1-2,4-7,16,29H,3,8-15H2

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00623
Curator's Comment: Description was created based on several sources, including

Fluphenazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Fluphenazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. Fluphenazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Carboxylesterase 8 Target ID: CHEMBL3383 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9755905	Substrate 661
Dopamine D2 receptor 297 Target ID: CHEMBL217 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2778
Serotonin 2c (5-HT2c) receptor 124 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11561066	Inverse Agonist 80	1.412 µM [EC50]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL1907610 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2879204	Antagonist 2778
Dopamine D1 receptor 101 Target ID: CHEMBL2056 Sources: http://www.drugbank.ca/drugs/DB00623	Antagonist 2778

Conditions

Condition	Modality	Targets	Highest Phase	Product
Schizophrenia 298 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/071413s019lbl.pdf	Primary		Approved 8429	FLUPHENAZINE DECANOATE Approved Use Fluphenazine Decanoate Injection is a longacting parenteral antipsychotic drug intended for use in the management of patients requiring prolonged parenteral neuroleptic therapy (e.g., chronic schizophrenics). Launch Date 1987

C_max

Value	Dose	Analyte	Population
2.3 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
261 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	2.5 mg 3 times / 3 days multiple, intravenous dose: 2.5 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
0.52 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
6.92 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
14.4 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
12.3 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/8911886	2.5 mg 3 times / 3 days multiple, intravenous dose: 2.5 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
13 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2313572	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:	FLUPHENAZINE plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.6% EXPERIMENT https://www.agilent.com/cs/library/applications/5991-2497EN.pdf			FLUPHENAZINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	Disc. AE: Akathisia, Dyskinesia... AEs leading to discontinuation/dose reduction: Akathisia (3.3%) Dyskinesia (3.3%) Hypertonia (3.3%) Stupor (3.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
250 mg 1 times / week multiple, intramuscular Highest studied dose Dose: 250 mg, 1 times / week Route: intramuscular Route: multiple Dose: 250 mg, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438	unhealthy, 44 n = 25 Health Status: unhealthy Condition: Schizophrenia Age Group: 44 Sex: M+F Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438	Sources: https://pubmed.ncbi.nlm.nih.gov/11760 Page: p.1438
100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	Disc. AE: Tardive dyskinesia, Neuroleptic malignant syndrome... AEs leading to discontinuation/dose reduction: Tardive dyskinesia Neuroleptic malignant syndrome Fall Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display

AEs

AE	Significance	Dose	Population
Akathisia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Dyskinesia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Hypertonia	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Stupor	3.3% Disc. AE	21 mg 1 times / day multiple, intramuscular (max) Recommended Dose: 21 mg, 1 times / day Route: intramuscular Route: multiple Dose: 21 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315	unhealthy, 35.4+/-10.4 n = 30 Health Status: unhealthy Condition: Schizophrenia Age Group: 35.4+/-10.4 Sex: M+F Population Size: 30 Sources: https://pubmed.ncbi.nlm.nih.gov/14751428 Page: p.315
Fall	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display
Neuroleptic malignant syndrome	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display
Tardive dyskinesia	Disc. AE	100 mg single, intramuscular\|subcutaneous Recommended Dose: 100 mg Route: intramuscular\|subcutaneous Route: single Dose: 100 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display	unhealthy Health Status: unhealthy Condition: Schizophrenia Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1967dc24-f2a5-4095-baa9-a9d1c5410311&type=display

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inhibitor 1587	inhibitor 1767	substrate 1217 inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524	CYP2C19 991

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	moderate [Ki 40.2 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 398.1 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://www.sciencedirect.com/science/article/abs/pii/S0009279704000250 Page: 5.0	weak [IC50 441.2 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://dmd.aspetjournals.org/content/27/9/1078.short	yes [Ki 9.4 uM]

Drug as victim

Target	Modality	Activity
CYP2C19 991	substrate 3367 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP2D6 1217	substrate 3367 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes
CYP3A4 1737	substrate 3367 Sources: https://www.jstage.jst.go.jp/article/cpb/60/12/60_c12-00719/_pdf/-char/en	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/23395964/ Page: 7.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5123	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5123
ChemicalBook	CB7107784	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7107784
MolPort	MolPort-001-727-938	https://www.molport.com/shop/molecule-link/MolPort-001-727-938
ZINC	ZINC000019203912	http://zinc15.docking.org/substances/ZINC000019203912
eMolecules	732810	https://www.emolecules.com/cgi-bin/more?vid=732810

PubMed

Title	Date	PubMed
Dystonic reactions to phenothiazine derivatives.	1966 Oct	5957732
[Psuedotetanus caused by neuroleptics. Description of a case caused by fluphenazine].	1966 Sep-Oct	5991322
Side-effects of phenothiazines.	1967 Apr 1	6021008
Drug-induced extrapyramidal symptoms: their incidence and treatment.	1967 Jan	6016862
Treatment of resistant schizophrenics with extreme high dosage fluphenazine hydrochloride.	1970 Sep-Oct	4919176
Side effects of parenteral long-acting phenothiazines.	1972 Jan 22	5058734
The therapeutic use of diazepam for akathisia.	1973 Jul-Aug	4795129
Maintenance treatment of schizophrenia with long-acting fluphenazine.	1974 Aug	4154028
Phenothiazine-induced decompensation.	1974 Jan	4587065
Schizophrenia-like reaction to diethylpropion.	1976 Nov 27	63037
Dystonic reaction to high dose propranolol.	1977 Oct 29	589060
Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings.	1978 Dec	31480
High vs standard dosage fluphenazine HCL in acute schizophrenia.	1978 Nov	363702
Phenothiazine-induced dystonic reaction while swimming.	1978 Oct 21	709286
The influence of alpha-adrenergic drugs on catalepsy induced by haloperidol or fluphenazine in rats.	1978 Sep-Oct	35783
Sleep disturbance associated with fluphenazine HCl: a case report.	1979 Jul	453364
Benztropine prophylaxis of dystonic reactions.	1979 Mar 28	36644
Delirium associated with combined fluphenazine-clonidine therapy.	1979 May	438148
behavior of rats and mice administered active metabolites of fluphenazine, 7-hydroxy-fluphenazine and fluphenazine-sulfoxide.	1980 Nov	7194019
Fluphenazine pharmacokinetics and therapeutic response.	1981	6787637
Neuroleptic-induced acute dyskinesias in rhesus monkeys.	1981	6117919
Intrauterine effect of phenothiazines.	1981 Apr 18	7254089
Stuttering: an unusual side effect of phenothiazines.	1981 Mar	6110346
Neuroleptic-induced seizures. An in vitro technique for assessing relative risk.	1982 Feb	6175290
Sexual dysfunction in women using major tranquilizers.	1982 Sep	7146292
A case of neuroleptic malignant syndrome successfully treated with amantadine.	1982 Sep	7118846
Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine.	1983 Jul	6614876
Occurrence of neuroleptic malignant syndrome in a narcoleptic patient.	1983 Jun	6134661
Neuroleptic malignant syndrome.	1984 Jan 7	6146918
[Malignant neuroleptics syndrome].	1984 Mar 9	6697897
Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes.	1984 Sep	6147851
[Catatonia due to fluphenazine].	1986 Apr 1	3732946
A case of neuroleptic malignant syndrome in a mentally retarded adolescent.	1986 Nov	3804828
Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain.	1987 Dec	2962686
Drug-induced dystonia in young and elderly patients.	1988 Jul	2898212
Manic syndrome associated with zidovudine treatment.	1988 Jun 17	3163740
[Repeated acute dystonia following administration of metoclopramide and fluphenazine].	1988 Mar 14	3354100
[Tardive dystonia--a case report on therapy and metaphylaxis].	1988 May	2905065
Interaction between fluoxetine and neuroleptics.	1993 May	8480836
Central effects of SL 82.0715, an antagonist of polyamine site of the NMDA receptor complex.	1993 Sep-Dec	7912135
The natural course of pseudotumor cerebri in lithium-treated patients.	1994 Aug	7962691
Relation of plasma fluphenazine levels to treatment response and extrapyramidal side effects in first-episode schizophrenic patients.	1994 Jan	8267132
Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.	1994 Mar	7908055
Effects of concomitant risperidone and lithium treatment.	1995 Jul	7540798
Some behavioral effects of CNQX AND NBQX, AMPA receptor antagonists.	1995 Jul-Aug	8616504
Fluphenazine plasma levels, dosage, efficacy, and side effects.	1995 May	7726317
Some central effects of GYKI 52466, a non-competitive AMPA receptor antagonist.	1995 Nov-Dec	8868372
Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of D-amphetamine.	1995 Sep 5	7498321
Roxindole, a potential antidepressant. I. Effect on the dopamine system.	1996	8811507
Tardive dyskinesia induced by risperidone?	1996 Jun	8633711

Patents

Sample Use Guides

In Vivo Use Guide

For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy.

Route of Administration: Intramuscular

In Vitro Use Guide

30uM Fluphenazine inhibited the high-threshold Ca2 channel current in rat sympathetic neurons (blocking by 66%).

Name

Type

Language

FLUPHENAZINE

Official Name

English

FLUPHENAZINE ENANTHATE IMPURITY B [EP IMPURITY]

Common Name

English

1-PIPERAZINEETHANOL, 4-(3-(2-(TRIFLUOROMETHYL)-10H-PHENOTHIAZIN-10-YL)PROPYL)-

Systematic Name

English

NSC-62323

Code

English

FLUPHENAZINE [MART.]

Common Name

English

FLUPHENAZINE [MI]

Common Name

English

FLUPHENAZINE ENANTATE IMPURITY B [EP IMPURITY]

Common Name

English

4-(3-(2-(TRIFLUOROMETHYL)PHENOTHIAZIN-10-YL)PROPYL)-1-PIPERAZINEETHANOL

Systematic Name

English

Fluphenazine [WHO-DD]

Common Name

English

FLUPHENAZINE [HSDB]

Common Name

English

fluphenazine [INN]

Common Name

English

FLUPHENAZINE [VANDF]

Common Name

English

MODITEN

Brand Name

English

FLUPHENAZINE DECANOATE IMPURITY B [EP IMPURITY]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000007544