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Identification
NamePerphenazine
Accession NumberDB00850  (APRD00429)
Typesmall molecule
Groupsapproved
Description

An antipsychotic phenothiazine derivative with actions and uses similar to those of chlorpromazine. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
2-(4-[3-(2-chloro-10H-Phenothiazin-10-yl)propyl]-1-piperazinyl)ethanolNot AvailableNot Available
2-chloro-10-(3-(4-(2-Hydroxyethyl)piperazin-1-yl)propyl)phenothiazineNot AvailableNot Available
4-[3-(2-chloro-10H-Phenothiazin-10-yl)propyl]-1-piperazineethanolNot AvailableNot Available
4-[3-(2-Chlorophenothiazin-10-yl)propyl]-1-piperazineethanolNot AvailableNot Available
ChlorpiprazineNot AvailableNot Available
EtaperazinNot AvailableNot Available
EtaperazineNot AvailableNot Available
EthaperazineNot AvailableNot Available
gamma-(4-(beta-Hydroxyethyl)piperazin-1-yl)propyl-2-chlorophenothiazineNot AvailableNot Available
PerfenazinaSpanishINN
PerfenazineNot AvailableNot Available
PerphenazinGermanINN
PerphénazineFrenchINN
PerphenazinumNot AvailableNot Available
TrilafonNot AvailableNot Available
Salts
Name/CAS Structure Properties
Perphenazine enanthate
Thumb Not applicable DBSALT000936
Perphenazine heptanoate
Thumb Not applicable DBSALT000937
Brand names
NameCompany
DecentanMerck
EmesinalNot Available
FentazinMercury
PerphenanTaro
PZCTanabe Mitsubishi Pharma
TrilafonSchering-Plough
TrilifanNot Available
Brand mixtures
Brand NameIngredients
Apo Peram Tab 2-25Amitriptyline Hydrochloride + Perphenazine
Apo Peram Tab 3-15Amitriptyline Hydrochloride + Perphenazine
Elavil Plus TabAmitriptyline Hydrochloride + Perphenazine
Etrafon 2 10Amitriptyline Hydrochloride + Perphenazine
Etrafon a TabAmitriptyline Hydrochloride + Perphenazine
Etrafon D TabAmitriptyline Hydrochloride + Perphenazine
Etrafon F TabAmitriptyline Hydrochloride + Perphenazine
Pms-Levazine 2/25 TabAmitriptyline Hydrochloride + Perphenazine
Pms-Levazine 3/15 TabAmitriptyline Hydrochloride + Perphenazine
Pms-Levazine 4/25 TabAmitriptyline Hydrochloride + Perphenazine
Proavil TabAmitriptyline Hydrochloride + Perphenazine
Triavil TabAmitriptyline Hydrochloride + Perphenazine
Categories
CAS number58-39-9
WeightAverage: 403.969
Monoisotopic: 403.148510866
Chemical FormulaC21H26ClN3OS
InChI KeyRGCVKNLCSQQDEP-UHFFFAOYSA-N
InChI
InChI=1S/C21H26ClN3OS/c22-17-6-7-21-19(16-17)25(18-4-1-2-5-20(18)27-21)9-3-8-23-10-12-24(13-11-23)14-15-26/h1-2,4-7,16,26H,3,8-15H2
IUPAC Name
2-{4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl}ethan-1-ol
SMILES
OCCN1CCN(CCCN2C3=CC=CC=C3SC3=C2C=C(Cl)C=C3)CC1
Mass Specshow(9.95 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzothiazines
SubclassPhenothiazines
Direct parentPhenothiazines
Alternative parentsChlorobenzenes; Aryl Chlorides; Diazinanes; Piperazines; Tertiary Amines; Primary Alcohols; Thioethers; Polyamines; Organochlorides
Substituentschlorobenzene; 1,4-diazinane; aryl halide; piperazine; benzene; aryl chloride; tertiary amine; thioether; polyamine; primary alcohol; amine; organohalogen; alcohol; organonitrogen compound; organochloride
Classification descriptionThis compound belongs to the phenothiazines. These are polycyclic aromatic compounds containing a phenothiazine moiety, which is a linear tricyclic system that consists of a two benzene rings joined by a para-thiazine ring.
Pharmacology
IndicationFor use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults.
PharmacodynamicsPerphenazine is a piperazinyl phenothiazine, acts on the central nervous system, and has a greater behavioral potency than other phenothiazine derivatives whose side chains do not contain a piperazine moiety. It is a member of a class of drugs called phenothiazines, which are dopamine D1/D2 receptor antagonists. Perphenazine is 10 to 15 times as potent as chlorpromazine; that means perphenazine is a highly potent antipsychotic. In equivalent doses it has approximately the same frequency and severity of early and late extrapypramidal side-effects compared to Haloperidol.
Mechanism of actionBinds to the dopamine D1 and dopamine D2 receptors and inhibits their activity. The mechanism of the anti-emetic effect is due predominantly to blockage of the dopamine D2 neurotransmitter receptors in the chemoreceptor trigger zone and vomiting centre. Perphenazine also binds the alpha andrenergic receptor. This receptor's action is mediated by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
AbsorptionAbsolute bioavailability is 40% following oral administration.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic.

Route of eliminationPerphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation.
Half life8-12 hours, but ranges up to 20 hours.
ClearanceNot Available
ToxicitySymptoms of overdose include stupor or coma, and children may have convulsive seizures. Signs of arousal may not occur for 48 hours. Oral LD50=318 mg/kg (rat); IPR LD50=64 mg/kg (mouse)
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 + 0.9476
Blood Brain Barrier + 0.9683
Caco-2 permeable - 0.5126
P-glycoprotein substrate Substrate 0.7862
P-glycoprotein inhibitor I Inhibitor 0.8563
P-glycoprotein inhibitor II Inhibitor 0.7689
Renal organic cation transporter Inhibitor 0.5807
CYP450 2C9 substrate Non-substrate 0.7442
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.6813
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.9278
CYP450 2C19 substrate Non-inhibitor 0.9026
CYP450 3A4 substrate Non-inhibitor 0.9089
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7548
Ames test Non AMES toxic 0.8093
Carcinogenicity Non-carcinogens 0.8836
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 3.0725 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7745
hERG inhibition (predictor II) Inhibitor 0.7066
Pharmacoeconomics
Manufacturers
  • Pharmaceutical assoc inc
  • Schering corp sub schering plough corp
  • Ivax pharmaceuticals inc
  • Sandoz inc
  • Vintage pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
LiquidOral
TabletOral
Prices
Unit descriptionCostUnit
Perphenazine 16 mg tablet1.73USDtablet
Perphenazine 8 mg tablet1.28USDtablet
Perphenazine 4 mg tablet1.05USDtablet
Perphenazine 2 mg tablet0.77USDtablet
Apo-Perphenazine 16 mg Tablet0.13USDtablet
Apo-Perphenazine 8 mg Tablet0.09USDtablet
Apo-Perphenazine 4 mg Tablet0.08USDtablet
Apo-Perphenazine 2 mg Tablet0.07USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point97 °CPhysProp
boiling point278-281 °C at 1.00E+00 mm HgPhysProp
water solubility28.3 mg/L (at 24 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP4.20HANSCH,C ET AL. (1995)
logS-4.16ADME Research, USCD
pKa7.94SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility2.37e-02 g/lALOGPS
logP4.15ALOGPS
logP3.69ChemAxon
logS-4.2ALOGPS
pKa (strongest acidic)15.59ChemAxon
pKa (strongest basic)8.21ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count1ChemAxon
polar surface area29.95ChemAxon
rotatable bond count6ChemAxon
refractivity116.1ChemAxon
polarizability44.77ChemAxon
number of rings4ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US2860138
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00503
KEGG CompoundC07427
PubChem Compound4748
PubChem Substance46507058
ChemSpider4586
ChEBI8028
ChEMBLCHEMBL567
Therapeutic Targets DatabaseDAP000100
PharmGKBPA450882
IUPHAR209
Guide to Pharmacology209
Drug Product Database726184
RxListhttp://www.rxlist.com/cgi/generic3/perphenazine.htm
Drugs.comhttp://www.drugs.com/cdi/perphenazine.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/tri1616.shtml
WikipediaPerphenazine
ATC CodesN05AB03
AHFS Codes
  • 28:16.08.24
PDB EntriesNot Available
FDA labelshow(360 KB)
MSDSshow(74.9 KB)
Interactions
Drug Interactions
Drug
AmphetamineDecreased anorexic effect, may increase psychotic symptoms
AtomoxetineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
BenzphetamineAntipsychotics may diminish the stimulatory effect of Amphetamines. Monitor effectiveness of amphetamine therapy when altering concurrent antipsychotic therapy as antipsychotic agents may impair the stimulatory effect of amphetamines.
BromocriptineThe phenothiazine decreases the effect of bromocriptine
CisaprideIncreased risk of cardiotoxicity and arrhythmias
DexfenfluramineDecreased anorexic effect, may increase psychotic symptoms
DextroamphetamineDecreased anorexic effect, may increase psychotic symptoms
DiethylpropionDecreased anorexic effect, may increase psychotic symptoms
DonepezilPossible antagonism of action
FenfluramineDecreased anorexic effect, may increase psychotic symptoms
GalantaminePossible antagonism of action
GatifloxacinIncreased risk of cardiotoxicity and arrhythmias
GrepafloxacinIncreased risk of cardiotoxicity and arrhythmias
GuanethidinePerphenazine may decrease the effect of guanethidine.
LevofloxacinIncreased risk of cardiotoxicity and arrhythmias
MazindolDecreased anorexic effect, may increase psychotic symptoms
MethamphetamineDecreased anorexic effect, may increase psychotic symptoms
MetrizamideIncreased risk of convulsions
PhendimetrazineDecreased anorexic effect, may increase psychotic symptoms
PhenmetrazineDecreased anorexic effect, may increase psychotic symptoms
PhentermineDecreased anorexic effect, may increase psychotic symptoms
PhenylpropanolamineDecreased anorexic effect, may increase psychotic symptoms
RivastigminePossible antagonism of action
SparfloxacinIncreased risk of cardiotoxicity and arrhythmias
TacrineThe therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Perphenazine, 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.
TerbinafineTerbinafine may reduce the metabolism and clearance of Perphenazine. Consider alternate therapy or monitor for therapeutic/adverse effects of Perphenazine if Terbinafine is initiated, discontinued or dose changed.
TerfenadineIncreased risk of cardiotoxicity and arrhythmias
TetrabenazineMay cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.
TrimethobenzamideTrimethobenzamide and Perphenazine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
TriprolidineThe antihistamine, Triprolidine, may increase the arrhythmogenic effect of the phenothiazine, Perphenazine. Monitor for symptoms of ventricular arrhythmias. Additive anticholinergic and CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
TrospiumTrospium and Perphenazine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
Food Interactions
  • Avoid alcohol.
  • Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
  • Take with food.

Targets

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. Seeman P: Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002 Feb;47(1):27-38. Pubmed
  2. Hoyberg OJ, Fensbo C, Remvig J, Lingjaerde O, Sloth-Nielsen M, Salvesen I: Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations. Acta Psychiatr Scand. 1993 Dec;88(6):395-402. Pubmed
  3. Qin ZH, Weiss B: Dopamine receptor blockade increases dopamine D2 receptor and glutamic acid decarboxylase mRNAs in mouse substantia nigra. Eur J Pharmacol. 1994 Sep 15;269(1):25-33. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  5. Talvik M, Nordstrom AL, Larsen NE, Jucaite A, Cervenka S, Halldin C, Farde L: A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration. Psychopharmacology (Berl). 2004 Sep;175(2):148-53. Epub 2004 Mar 6. Pubmed
  6. Farde L, Wiesel FA, Nordstrom AL, Sedvall G: D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berl). 1989;99 Suppl:S28-31. Pubmed

2. 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. Dolzan V, Plesnicar BK, Serretti A, Mandelli L, Zalar B, Koprivsek J, Breskvar K: Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. Am J Med Genet B Neuropsychiatr Genet. 2007 Sep 5;144(6):809-15. Pubmed
  2. Farde L, Wiesel FA, Nordstrom AL, Sedvall G: D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berl). 1989;99 Suppl:S28-31. Pubmed

3. Calmodulin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Calmodulin P62158 Details

References:

  1. Mongin AA, Cai Z, Kimelberg HK: Volume-dependent taurine release from cultured astrocytes requires permissive [Ca(2+)](i) and calmodulin. Am J Physiol. 1999 Oct;277(4 Pt 1):C823-32. Pubmed
  2. Kawai M, Nakashima A, Ueno M, Ushimaru T, Aiba K, Doi H, Uritani M: Fission yeast tor1 functions in response to various stresses including nitrogen starvation, high osmolarity, and high temperature. Curr Genet. 2001 May;39(3):166-74. Pubmed
  3. Edlind T, Smith L, Henry K, Katiyar S, Nickels J: Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling. Mol Microbiol. 2002 Oct;46(1):257-68. Pubmed
  4. Natochin YuV, Shakhmatova EI, Bakos P: Water and sodium transport: effects of calcium channel blocker and calmodulin antagonists on the apical and basolateral membranes of amphibian epithelia. Gen Physiol Biophys. 1987 Feb;6(1):35-44. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Otani K, Aoshima T: Pharmacogenetics of classical and new antipsychotic drugs. Ther Drug Monit. 2000 Feb;22(1):118-21. Pubmed
  2. Micallef J, Fakra E, Blin O: [Use of antidepressant drugs in schizophrenic patients with depression] Encephale. 2006 Mar-Apr;32(2 Pt 1):263-9. Pubmed
  3. Linnet K, Wiborg O: Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin Pharmacol Ther. 1996 Jul;60(1):41-7. Pubmed
  4. Ozdemir V, Naranjo CA, Herrmann N, Reed K, Sellers EM, Kalow W: Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther. 1997 Sep;62(3):334-47. Pubmed
  5. Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J: In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos. 1998 Jun;26(6):536-9. Pubmed
  6. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  7. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2C18

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C18 P33260 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

8. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 22, 2013 22:48