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Identification
NameLoxapine
Accession NumberDB00408  (APRD00574)
Typesmall molecule
Groupsapproved
Description

An antipsychotic agent used in schizophrenia. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepineNot AvailableWHO
LoxapinaNot AvailableDCIT
LoxapineNot AvailableINN, BAN, USAN
LoxapinumLatinINN
oxilapineNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AdasuveNot Available
CloxazepineNot Available
LopacNewai Chem
LosagenPatron
LoxapacWyeth
LoxapineHisun
LoxitaneNot Available
RosupSwiss Pharm
Brand mixturesNot Available
Categories
CAS number1977-10-2
WeightAverage: 327.808
Monoisotopic: 327.11383992
Chemical FormulaC18H18ClN3O
InChI KeyInChIKey=XJGVXQDUIWGIRW-UHFFFAOYSA-N
InChI
InChI=1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3
IUPAC Name
13-chloro-10-(4-methylpiperazin-1-yl)-2-oxa-9-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,9,12,14-heptaene
SMILES
CN1CCN(CC1)C1=NC2=CC=CC=C2OC2=C1C=C(Cl)C=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzoxazepines
SubclassDibenzoxazepines
Direct parentDibenzoxazepines
Alternative parentsDiarylethers; Chlorobenzenes; Piperazines; Aryl Chlorides; Diazinanes; Tertiary Amines; Polyamines; Carboxamidines; Organochlorides
Substituentsdiaryl ether; chlorobenzene; 1,4-diazinane; aryl halide; aryl chloride; benzene; piperazine; tertiary amine; polyamine; carboxylic acid amidine; ether; amidine; organohalogen; organochloride; organonitrogen compound; amine
Classification descriptionThis compound belongs to the dibenzoxazepines. These are compounds containing a dibenzoxazepine moiety, which consists of two benzene connected by an oxazepine ring.
Pharmacology
IndicationFor the management of the manifestations of psychotic disorders such as schizophrenia
PharmacodynamicsLoxapine, a dibenzoxazepine compound, represents a subclass of tricyclic antipsychotic agents, chemically distinct from the thioxanthenes, butyrophenones, and phenothiazines. Pharmacologically, Loxapine is a tranquilizer for which the exact mode of action has not been established, however, it is believed that by antagonising dopamine and serotonin receptors, there is a marked cortical inhibition which can manifest as tranquilization and suppression of aggression.
Mechanism of actionLoxapine is a dopamine antagonist, and also a serotonin 5-HT2 blocker. The exact mode of action of Loxapine has not been established, however changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species in association with such manifestations of tranquilization as calming effects and suppression of aggressive behavior.
AbsorptionSystemic bioavailability of the parent drug was only about one third that after an equivalent intramuscular dose (25 mg base) in male volunteers
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationMetabolites are excreted in the urine in the form of conjugates and in the feces unconjugated.
Half lifeOral-4 hours
ClearanceNot Available
ToxicityLD50=65 mg/kg (Orally in mice)
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 + 0.9944
Blood Brain Barrier + 0.9801
Caco-2 permeable + 0.5531
P-glycoprotein substrate Substrate 0.8545
P-glycoprotein inhibitor I Inhibitor 0.8525
P-glycoprotein inhibitor II Inhibitor 0.8388
Renal organic cation transporter Inhibitor 0.7084
CYP450 2C9 substrate Non-substrate 0.7331
CYP450 2D6 substrate Substrate 0.7155
CYP450 3A4 substrate Substrate 0.6309
CYP450 1A2 substrate Inhibitor 0.8159
CYP450 2C9 substrate Non-inhibitor 0.8755
CYP450 2D6 substrate Inhibitor 0.7543
CYP450 2C19 substrate Non-inhibitor 0.6217
CYP450 3A4 substrate Non-inhibitor 0.9393
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6968
Ames test Non AMES toxic 0.9133
Carcinogenicity Non-carcinogens 0.8743
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 3.3057 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.5701
hERG inhibition (predictor II) Inhibitor 0.6141
Pharmacoeconomics
Manufacturers
  • Watson laboratories inc
  • Actavis totowa llc
  • Mylan pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
LiquidIntramuscular
SolutionOral
TabletOral
Prices
Unit descriptionCostUnit
Loxapac 50 mg/ml7.05USDml
Loxitane 50 mg capsule4.04USDcapsule
Loxitane 25 mg capsule3.09USDcapsule
Loxapine 50 mg capsule2.57USDcapsule
Loxitane 10 mg capsule2.04USDcapsule
Loxapine 25 mg capsule1.92USDcapsule
Loxitane 5 mg capsule1.58USDcapsule
Loxapine 10 mg capsule1.27USDcapsule
Loxapine Succinate 5 mg capsule1.03USDcapsule
Loxapine 5 mg capsule0.99USDcapsule
Pms-Loxapine 50 mg Tablet0.54USDtablet
Pms-Loxapine 25 mg Tablet0.41USDtablet
Pms-Loxapine 10 mg Tablet0.26USDtablet
Pms-Loxapine 5 mg Tablet0.16USDtablet
Pms-Loxapine 2.5 mg Tablet0.08USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point109-110 °CPhysProp
logP3.6Not Available
Predicted Properties
PropertyValueSource
water solubility1.03e-01 g/lALOGPS
logP3.18ALOGPS
logP3.46ChemAxon
logS-3.5ALOGPS
pKa (strongest basic)7.18ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count0ChemAxon
polar surface area28.07ChemAxon
rotatable bond count0ChemAxon
refractivity95.11ChemAxon
polarizability34.99ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US3412193
General Reference
  1. Glazer WM: Does loxapine have “atypical” properties? Clinical evidence. J Clin Psychiatry. 1999;60 Suppl 10:42-6. Pubmed
  2. Cheung SW, Tang SW, Remington G: Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography. J Chromatogr. 1991 Mar 8;564(1):213-21. Pubmed
External Links
ResourceLink
KEGG DrugD02340
KEGG CompoundC07104
PubChem Compound3964
PubChem Substance46505047
ChemSpider3827
BindingDB22871
ChEBI50841
ChEMBLCHEMBL831
Therapeutic Targets DatabaseDAP000311
PharmGKBPA450273
IUPHAR205
Guide to Pharmacology205
Drug Product Database2255448
RxListhttp://www.rxlist.com/cgi/generic2/loxapineoc.htm
Drugs.comhttp://www.drugs.com/cdi/loxapine.html
WikipediaLoxapine
ATC CodesN05AH01
AHFS Codes
  • 28:16.08.92
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
RotigotinePharmacodynamic antagonism may decrease the effects of rotigotine. Consider alternate therapy.
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Loxapine, 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.
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 Loxapine, 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 Loxapine, 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 Loxapine, 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
  • Take with food to reduce irritation. Avoid alcohol.

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. Lee T, Tang SW: Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Res. 1984 Aug;12(4):277-85. Pubmed
  2. Hjerde E, Dahl SG, Sylte I: Atypical and typical antipsychotic drug interactions with the dopamine D2 receptor. Eur J Med Chem. 2005 Feb;40(2):185-94. Pubmed
  3. Kalkman HO, Neumann V, Nozulak J, Tricklebank MD: Cataleptogenic effect of subtype selective 5-HT receptor antagonists in the rat. Eur J Pharmacol. 1998 Feb 19;343(2-3):201-7. Pubmed
  4. Froimowitz M, Cody V: Biologically active conformers of phenothiazines and thioxanthenes. Further evidence for a ligand model of dopamine D2 receptor antagonists. J Med Chem. 1993 Jul 23;36(15):2219-27. Pubmed
  5. Froimowitz M, Cody V: The incorporation of butyrophenones and related compounds into a pharmacophore for dopamine D2 antagonists. Drug Des Discov. 1997 Aug;15(2):63-81. Pubmed
  6. Lang AE, Sandor P, Duff J: Remoxipride in Parkinson’s disease: differential response in patients with dyskinesias fluctuations versus psychosis. Clin Neuropharmacol. 1995 Feb;18(1):39-45. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. D(1A) dopamine receptor

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

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

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

3. 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. Li Z, Ichikawa J, Meltzer HY: A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens. Psychopharmacology (Berl). 2003 May;167(3):315-23. Epub 2003 Mar 28. Pubmed

4. 5-hydroxytryptamine receptor 2C

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: antagonist

Components

Name UniProt ID Details
5-hydroxytryptamine receptor 2C P28335 Details

References:

  1. Herrick-Davis K, Grinde E, Teitler M: Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors. J Pharmacol Exp Ther. 2000 Oct;295(1):226-32. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on January 21, 2014 21:04