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Identification
NameFlupentixol
Accession NumberDB00875  (APRD00388)
Typesmall molecule
Groupsapproved, withdrawn
Description

Flupentixol is an antipsychotic neuroleptic drug. It is a thioxanthene, and therefore closely related to the phenothiazines. Its primary use is as a long acting injection given two or three weekly to people with schizophrenia who have a poor compliance with medication and suffer frequent relapses of illness. It is a D1 and D2 receptor antagonist. It is not approved in the United States.

Structure
Thumb
Synonyms
SynonymLanguageCode
FlupenthixolNot AvailableNot Available
FlupenthixoleNot AvailableNot Available
FlupentixolGermanNot Available
FlupentixolFrenchNot Available
FlupentixolSpanishNot Available
FlupentixoloNot AvailableOS: DCIT
FlupentixolumLatinNot Available
Salts
Name/CAS Structure Properties
Flupentixol Decanoate
Thumb Not applicable DBSALT000928
Flupentixol Hydrochloride
Thumb Not applicable DBSALT000929
Brand names
NameCompany
DepixolLundbeck A/S
FluanxolLundbeck A/S
JexitJohnson
Brand mixtures
Brand NameIngredients
AnxisetFlupentixol and Melitracen
DeanxitFlupentixol and Melitracen
FrenxitFlupentixol and Melitracen
MixitFlupentixol and Melitracen
MocalmFlupentixol and Melitracen
Categories
CAS number2709-56-0
WeightAverage: 436.533
Monoisotopic: 436.179618801
Chemical FormulaC23H27F3N2OS
InChI KeyInChIKey=DTTVNHWDONBIKE-DVZOWYKESA-N
InChI
InChI=1S/C23H27F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,20,22,29H,3,9-15H2/b18-5-
IUPAC Name
2-(4-{3-[2-(trifluoromethyl)-9,9a-dihydro-4aH-thioxanthen-9-ylidene]propyl}piperazin-1-yl)ethan-1-ol
SMILES
[H]C(CCN1CCN(CCO)CC1)=C1C2C=C(C=CC2SC2=C1C=CC=C2)C(F)(F)F
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzopyrans
SubclassThioxanthenes
Direct parentThioxanthenes
Alternative parentsThiochromanes; Thiopyrans; Benzene and Substituted Derivatives; Diazinanes; Piperazines; Tertiary Amines; Polyamines; Primary Alcohols; Thioethers; Organofluorides; Alkyl Fluorides
Substituentsthiochromane; thiopyran; 1,4-diazinane; benzene; piperazine; tertiary amine; polyamine; thioether; primary alcohol; organonitrogen compound; amine; alcohol; organofluoride; organohalogen; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the thioxanthenes. These are organic polycyclic compounds containing a thioxanthene moiety, which is an aromatic tricycle derived from xanthene by replacing the oxygen atom with a sulfur atom.
Pharmacology
IndicationFor use in the treatment of schizophrenia and depression
PharmacodynamicsFlupenthixol is an anxiolytic, antidepressive agent and a mood stabilizer. It inhibits the central monoamine receptors, particularly the dopamine D1 and D2 receptors. Therefore, it increases the amount of serotonin and noradrenaline that control mood and thinking, and improves mood.
Mechanism of actionFlupenthixol is a thioxanthene antipsychotic. The mechanism of action of Flupenthixol is not completely understood. Flupenthixol is a powerful antagonist of both D1 and D2 dopamine receptors, and an alpha-adrenergic receptor antagonist. It's antipsychotic activity is thought to be related to blocks postsynaptic dopamine receptors in the CNS.
AbsorptionFairly slow and incomplete after oral administration
Volume of distributionNot Available
Protein bindingHighly bound to plasma proteins (>95%)
Metabolism

Mainly hepatic

Route of eliminationNot Available
Half life19 to 39 hours
ClearanceNot Available
ToxicityLD50=300 mk/kg (Oral in mice); LD50=791 mg/kg (Oral in rats); LD50=87 mk/kg (IV in mice); LD50=37 mg/kg (IV in rats)
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9825
Blood Brain Barrier + 0.9778
Caco-2 permeable - 0.5438
P-glycoprotein substrate Substrate 0.8762
P-glycoprotein inhibitor I Inhibitor 0.92
P-glycoprotein inhibitor II Inhibitor 0.859
Renal organic cation transporter Inhibitor 0.5065
CYP450 2C9 substrate Non-substrate 0.8084
CYP450 2D6 substrate Substrate 0.804
CYP450 3A4 substrate Non-substrate 0.6921
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8933
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Inhibitor 0.5657
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7748
Ames test Non AMES toxic 0.828
Carcinogenicity Non-carcinogens 0.8985
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.8385 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6624
hERG inhibition (predictor II) Inhibitor 0.7962
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Fluanxol Depot 100 mg/ml39.79USDml
Fluanxol Depot 20 mg/ml7.96USDml
Fluanxol 3 mg Tablet0.59USDtablet
Fluanxol 0.5 mg Tablet0.27USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubility0.000346 mg/mlNot Available
logP4.51HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
water solubility3.00e-03 g/lALOGPS
logP4.12ALOGPS
logP3.54ChemAxon
logS-5.2ALOGPS
pKa (strongest acidic)15.59ChemAxon
pKa (strongest basic)8.51ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count1ChemAxon
polar surface area26.71ChemAxon
rotatable bond count6ChemAxon
refractivity120.93ChemAxon
polarizability45.28ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD01044
ChEBI5121
ChEMBLCHEMBL54661
Therapeutic Targets DatabaseDAP000026
PharmGKBPA10268
IUPHAR968
Guide to Pharmacology968
Drug Product Database2156016
Drugs.comhttp://www.drugs.com/international/flupentixol.html
WikipediaFlupenthixol
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
DonepezilPossible antagonism of action
GalantaminePossible antagonism of action
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
RivastigminePossible antagonism of action
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Flupenthixol, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TetrabenazineMay cause dopamine deficiency. Monitor for Tetrabenazine adverse effects. Similar pharmacologic properties thus combination therapy will worsen the severity of sedative, parkinsonian, and extrapyramidal adverse effects.
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TrimethobenzamideTrimethobenzamide and Flupenthixol, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TriprolidineTriprolidine and Flupenthixol, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
TrospiumTrospium and Flupenthixol, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
VoriconazoleAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol decanoateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Avoid alcohol.
  • Take with food to reduce irritation.

1. D(2) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(2) dopamine receptor P14416 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. Pubmed
  3. Ogren SO, Hall H, Kohler C, Magnusson O, Lindbom LO, Angeby K, Florvall L: Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain. Eur J Pharmacol. 1984 Jul 20;102(3-4):459-74. Pubmed
  4. Arnt J: Differential effects of classical and newer antipsychotics on the hypermotility induced by two dose levels of D-amphetamine. Eur J Pharmacol. 1995 Sep 5;283(1-3):55-62. Pubmed
  5. Huettl P, Gerhardt GA, Browning MD, Masserano JM: Effects of dopamine receptor agonists and antagonists on catecholamine release in bovine chromaffin cells. J Pharmacol Exp Ther. 1991 May;257(2):567-74. Pubmed
  6. Nilsson CL, Ekman A, Hellstrand M, Eriksson E: Inverse agonism at dopamine D2 receptors. Haloperidol-induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R(-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine. Neuropsychopharmacology. 1996 Jul;15(1):53-61. Pubmed
  7. Reimold M, Solbach C, Noda S, Schaefer JE, Bartels M, Beneke M, Machulla HJ, Bares R, Glaser T, Wormstall H: Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology (Berl). 2007 Feb;190(2):241-9. Epub 2006 Nov 17. Pubmed

2. 5-hydroxytryptamine receptor 2A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2A P28223 Details

References:

  1. Reimold M, Solbach C, Noda S, Schaefer JE, Bartels M, Beneke M, Machulla HJ, Bares R, Glaser T, Wormstall H: Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology (Berl). 2007 Feb;190(2):241-9. Epub 2006 Nov 17. Pubmed

3. D(1A) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
D(1A) dopamine receptor P21728 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Cai G, Gurdal H, Smith C, Wang HY, Friedman E: Inverse agonist properties of dopaminergic antagonists at the D(1A) dopamine receptor: uncoupling of the D(1A) dopamine receptor from G(s) protein. Mol Pharmacol. 1999 Nov;56(5):989-96. Pubmed
  4. Reimold M, Solbach C, Noda S, Schaefer JE, Bartels M, Beneke M, Machulla HJ, Bares R, Glaser T, Wormstall H: Occupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol. Psychopharmacology (Berl). 2007 Feb;190(2):241-9. Epub 2006 Nov 17. Pubmed

4. Alpha-1A adrenergic receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Alpha-1A adrenergic receptor P35348 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

5. Muscarinic acetylcholine receptor M1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details

References:

  1. Golds PR, Przyslo FR, Strange PG: The binding of some antidepressant drugs to brain muscarinic acetylcholine receptors. Br J Pharmacol. 1980 Mar;68(3):541-9. Pubmed

1. Aromatic-L-amino-acid decarboxylase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Aromatic-L-amino-acid decarboxylase P20711 Details

References:

  1. Zhu MY, Juorio AV, Paterson IA, Boulton AA: Regulation of aromatic L-amino acid decarboxylase in rat striatal synaptosomes: effects of dopamine receptor agonists and antagonists. Br J Pharmacol. 1994 May;112(1):23-30. Pubmed

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Hait WN, Gesmonde JF, Murren JR, Yang JM, Chen HX, Reiss M: Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. Biochem Pharmacol. 1993 Jan 26;45(2):401-6. Pubmed
  2. Dey S, Hafkemeyer P, Pastan I, Gottesman MM: A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol. Biochemistry. 1999 May 18;38(20):6630-9. Pubmed
  3. Hafkemeyer P, Licht T, Pastan I, Gottesman MM: Chemoprotection of hematopoietic cells by a mutant P-glycoprotein resistant to a potent chemosensitizer of multidrug-resistant cancers. Hum Gene Ther. 2000 Mar 1;11(4):555-65. Pubmed
  4. Yang JM, Vassil A, Hait WN: Involvement of phosphatidylinositol-3-kinase in membrane ruffling induced by P-glycoprotein substrates in multidrug-resistant carcinoma cells. Biochem Pharmacol. 2002 Mar 1;63(5):959-66. Pubmed
  5. Ford JM, Bruggemann EP, Pastan I, Gottesman MM, Hait WN: Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. Cancer Res. 1990 Mar 15;50(6):1748-56. Pubmed
  6. Ford JM, Yang JM, Hait WN: Effect of buthionine sulfoximine on toxicity of verapamil and doxorubicin to multidrug resistant cells and to mice. Cancer Res. 1991 Jan 1;51(1):67-72. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on October 18, 2013 13:39