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targets (3) enzymes (8)
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Identification
Name Perphenazine
Accession Number DB00850 (APRD00429)
Type small molecule
Groups approved
Description

An antipsychotic phenothiazine derivative with actions and uses similar to those of chlorpromazine. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlorperphenazine
  • Etaperazin
  • Etaperazine
  • Ethaperazine
  • Perfenazina
  • Perfenazine
  • Perphenazin
  • PZC
Brand names
  • Apo-Perphenazine
  • Decentan
  • Emesinal
  • Etrafon-A
  • Etrafon-Forte
  • F-Mon
  • Fentazin
  • Perphenan
  • Thilatazin
  • Trifaron
  • Trilafon
  • Trilifan
  • Triphenot
Brand name mixtures
  • Apo Peram Tab 2-25 (Amitriptyline Hydrochloride + Perphenazine)
  • Apo Peram Tab 3-15 (Amitriptyline Hydrochloride + Perphenazine)
  • Elavil Plus Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Etrafon 2 10 (Amitriptyline Hydrochloride + Perphenazine)
  • Etrafon a Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Etrafon D Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Etrafon F Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Pms-Levazine 2/25 Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Pms-Levazine 3/15 Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Pms-Levazine 4/25 Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Proavil Tab (Amitriptyline Hydrochloride + Perphenazine)
  • Triavil Tab (Amitriptyline Hydrochloride + Perphenazine)
Categories
  • Antipsychotics
  • Dopamine Antagonists
  • Phenothiazines
  • Antipsychotic Agents
CAS number 58-39-9
Weight Average: 403.969
Monoisotopic: 403.148510866
Chemical Formula C21H26ClN3OS
InChI Key InChIKey=RGCVKNLCSQQDEP-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
Plain Text
IUPAC Name
2-{4-[3-(2-chloro-10H-phenothiazin-10-yl)propyl]piperazin-1-yl}ethan-1-ol
SMILES
OCCN1CCN(CCCN2C3=C(SC4=C2C=C(Cl)C=C4)C=CC=C3)CC1
Plain Text
Mass Spec show (10 KB)
Taxonomy
Kingdom Organic
Classes
  • Phenothiazines
Substructures
  • Ethers
  • Hydroxy Compounds
  • Phenothiazines
  • Aliphatic and Aryl Amines
  • Piperazines
  • Thiazines
  • Benzene and Derivatives
  • Aryl Halides
  • Halobenzenes
  • Alcohols and Polyols
  • Heterocyclic compounds
  • Aromatic compounds
  • Anilines
Pharmacology
Indication For use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults.
Pharmacodynamics Perphenazine 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 action Binds 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.
Absorption Absolute bioavailability is 40% following oral administration.
Volume of distribution Not Available
Protein binding Not Available
Metabolism

Hepatic.
Route of elimination Perphenazine is extensively metabolized in the liver to a number of metabolites by sulfoxidation, hydroxylation, dealkylation, and glucuronidation.
Half life 8-12 hours, but ranges up to 20 hours.
Clearance Not Available
Toxicity Symptoms 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Pharmaceutical assoc inc
  • Schering corp sub schering plough corp
  • Ivax pharmaceuticals inc
  • Sandoz inc
  • Vintage pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Liquid Oral
Tablet Oral
Prices
Unit description Cost Unit
Perphenazine 16 mg tablet 1.73 USD tablet
Perphenazine 8 mg tablet 1.28 USD tablet
Perphenazine 4 mg tablet 1.05 USD tablet
Perphenazine 2 mg tablet 0.77 USD tablet
Apo-Perphenazine 16 mg Tablet 0.13 USD tablet
Apo-Perphenazine 8 mg Tablet 0.09 USD tablet
Apo-Perphenazine 4 mg Tablet 0.08 USD tablet
Apo-Perphenazine 2 mg Tablet 0.07 USD tablet
Patents Not Available
Properties
State solid
Melting point 97 oC
Experimental Properties
Property Value Source
water solubility 28.3 mg/L PhysProp
logP 3.9 PhysProp
logS -4.16 [ADME Research, USCD] PhysProp
pKa 7.94 Various sources
Predicted Properties
Property Value Source
water solubility 2.37e-02 g/l ALOGPS
logP 4.15 ALOGPS
logP 3.69 ChemAxon Molconvert
logS -4.23 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 4 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 29.95 ChemAxon Molconvert
rotatable bond count 6 ChemAxon Molconvert
refractivity 116.10 ChemAxon Molconvert
polarizability 44.77 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00503 Link_out
KEGG Compound C07427 Link_out
PubChem Compound 4748 Link_out
PubChem Substance 46507058 Link_out
ChemSpider 4586 Link_out
ChEBI 8028 Link_out
ChEMBL 8028 Link_out
Therapeutic Targets Database DAP000100 Link_out
PharmGKB PA450882 Link_out
Drug Product Database 726184 Link_out
RxList http://www.rxlist.com/cgi/generic3/perphenazine.htm Link_out
Drugs.com http://www.drugs.com/cdi/perphenazine.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/tri1616.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Perphenazine Link_out
ATC Codes
  • N05AB03
AHFS Codes
  • 28:16.08.24
PDB Entries Not Available
FDA label show (360.1 KB)
MSDS show (74.9 KB)
Interactions
Drug Interactions Not Available
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

Pharmacological action: yes
Actions: antagonist

This is one of the five types (D1 to D5) of receptors for dopamine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase

Organism class: human
UniProt ID: P14416 Link_out
Gene: DRD2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: antagonist

This is one of the five types (D1 to D5) of receptors for dopamine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase

Organism class: human
UniProt ID: P21728 Link_out
Gene: DRD1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: unknown
Actions: inhibitor

Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases

Organism class: human
UniProt ID: P62158 Link_out
Gene: CALM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P33260 Link_out
Gene: CYP2C18 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:06

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.