Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C21H26ClN3OS |
| Molecular Weight | 403.969 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
OCCN1CCN(CCCN2C3=CC=CC=C3SC4=CC=C(Cl)C=C24)CC1
InChI
InChIKey=RGCVKNLCSQQDEP-UHFFFAOYSA-N
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
Perphenazine is a relatively high potency phenothiazine that blocks dopamine 2 receptors predominantly, but also may possess antagonist actions at histamine 1 and cholinergic M1 and alpha 1 adrenergic receptors in the vomiting center leading to reduced nausea and vomiting. The drug was approved by FDA for the treatment of schizophrenia and control of severe nausea and vomiting (either alone or in combination with amitriptyline hydrochloride). Perphenazine is extensively hepatic to metabolites via sulfoxidation, hydroxylation, dealkylation, and glucuronidation; primarily metabolized by CYP2D6 to N-dealkylated perphenazine, perphenazine sulfoxide, and 7-hydroxyperphenazine (active metabolite with 70% of the activity of perphenazine) and excreted in the urine and feces.
CNS Activity
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: P14416 Gene ID: 1813.0 Gene Symbol: DRD2 Target Organism: Homo sapiens (Human) Sources: http://apm.amegroups.com/article/view/1039/1266 |
0.16 nM [Ki] | ||
Target ID: P35367 Gene ID: 3269.0 Gene Symbol: HRH1 Target Organism: Homo sapiens (Human) Sources: http://apm.amegroups.com/article/view/1039/1266 |
8.0 nM [Kd] | ||
Target ID: P11229 Gene ID: 1128.0 Gene Symbol: CHRM1 Target Organism: Homo sapiens (Human) Sources: http://apm.amegroups.com/article/view/1039/1266 |
1.5 µM [Kd] | ||
Target ID: CHEMBL2094251 Sources: http://apm.amegroups.com/article/view/1039/1266 |
10.0 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Preventing | PERPHENAZINE Approved UsePerphenazine is indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. Launch Date1988 |
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| Preventing | PERPHENAZINE Approved UsePerphenazine is indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. Launch Date1988 |
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| Primary | PERPHENAZINE Approved UsePerphenazine is indicated for use in the treatment of schizophrenia and for the control of severe nausea and vomiting in adults. Launch Date1988 |
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| Primary | PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE Approved UsePerphenazine and amitriptyline hydrochloride tablets are recommended for treatment of (1) patients with moderate to severe anxiety and/or agitation and depressed mood, (2) patients with depression in whom anxiety and/or agitation are severe, and (3) patients with depression and anxiety in association with chronic physical disease. In many of these patients, anxiety masks the depressive state so that, although therapy with a tranquilizer appears to be indicated, the administration of a tranquilizer alone will not be adequate. Launch Date1988 |
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| Primary | PERPHENAZINE AND AMITRIPTYLINE HYDROCHLORIDE Approved UsePerphenazine and amitriptyline hydrochloride tablets are recommended for treatment of (1) patients with moderate to severe anxiety and/or agitation and depressed mood, (2) patients with depression in whom anxiety and/or agitation are severe, and (3) patients with depression and anxiety in association with chronic physical disease. In many of these patients, anxiety masks the depressive state so that, although therapy with a tranquilizer appears to be indicated, the administration of a tranquilizer alone will not be adequate. Launch Date1988 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
0.546 ng/mL |
16 mg single, oral dose: 16 mg route of administration: Oral experiment type: SINGLE co-administered: |
PERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
|
984 pg/mL |
4 mg 3 times / day steady-state, oral dose: 4 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
|
509 pg/mL |
4 mg 3 times / day steady-state, oral dose: 4 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
7-HYDROXYPERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
6.673 ng × h/mL |
16 mg single, oral dose: 16 mg route of administration: Oral experiment type: SINGLE co-administered: |
PERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
9.12 h |
16 mg single, oral dose: 16 mg route of administration: Oral experiment type: SINGLE co-administered: |
PERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
|
12 h |
4 mg 3 times / day steady-state, oral dose: 4 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
|
18.8 h |
4 mg 3 times / day steady-state, oral dose: 4 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
7-HYDROXYPERPHENAZINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
9% |
unknown, unknown |
PERPHENAZINE unknown | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
0.93 g single, oral Overdose |
unhealthy, 42 |
Disc. AE: QT interval prolonged, Hypothermia... AEs leading to discontinuation/dose reduction: QT interval prolonged Sources: Hypothermia Loss of consciousness PR interval prolonged QRS prolonged |
200 mg single, oral Overdose |
unhealthy, 48 |
Disc. AE: Coma, Hypothermia... AEs leading to discontinuation/dose reduction: Coma Sources: Hypothermia Tachycardia Miosis |
30 mg 1 times / day multiple, intramuscular Recommended Dose: 30 mg, 1 times / day Route: intramuscular Route: multiple Dose: 30 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
Disc. AE: Tardive dyskinesia... AEs leading to discontinuation/dose reduction: Tardive dyskinesia Sources: |
30 mg 1 times / day multiple, intramuscular Recommended Dose: 30 mg, 1 times / day Route: intramuscular Route: multiple Dose: 30 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
Disc. AE: Neuroleptic malignant syndrome... AEs leading to discontinuation/dose reduction: Neuroleptic malignant syndrome Sources: |
64 mg 1 times / day multiple, oral Recommended Dose: 64 mg, 1 times / day Route: oral Route: multiple Dose: 64 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
Disc. AE: Tardive dyskinesia... AEs leading to discontinuation/dose reduction: Tardive dyskinesia Sources: |
64 mg 1 times / day multiple, oral Recommended Dose: 64 mg, 1 times / day Route: oral Route: multiple Dose: 64 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
Disc. AE: Neuroleptic malignant syndrome... AEs leading to discontinuation/dose reduction: Neuroleptic malignant syndrome Sources: |
20 mg single, intramuscular Studied dose Dose: 20 mg Route: intramuscular Route: single Dose: 20 mg Sources: |
unhealthy |
Disc. AE: Neuroleptic malignant syndrome... AEs leading to discontinuation/dose reduction: Neuroleptic malignant syndrome Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Hypothermia | Disc. AE | 0.93 g single, oral Overdose |
unhealthy, 42 |
| Loss of consciousness | Disc. AE | 0.93 g single, oral Overdose |
unhealthy, 42 |
| PR interval prolonged | Disc. AE | 0.93 g single, oral Overdose |
unhealthy, 42 |
| QRS prolonged | Disc. AE | 0.93 g single, oral Overdose |
unhealthy, 42 |
| QT interval prolonged | Disc. AE | 0.93 g single, oral Overdose |
unhealthy, 42 |
| Coma | Disc. AE | 200 mg single, oral Overdose |
unhealthy, 48 |
| Hypothermia | Disc. AE | 200 mg single, oral Overdose |
unhealthy, 48 |
| Miosis | Disc. AE | 200 mg single, oral Overdose |
unhealthy, 48 |
| Tachycardia | Disc. AE | 200 mg single, oral Overdose |
unhealthy, 48 |
| Tardive dyskinesia | Disc. AE | 30 mg 1 times / day multiple, intramuscular Recommended Dose: 30 mg, 1 times / day Route: intramuscular Route: multiple Dose: 30 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
| Neuroleptic malignant syndrome | Disc. AE | 30 mg 1 times / day multiple, intramuscular Recommended Dose: 30 mg, 1 times / day Route: intramuscular Route: multiple Dose: 30 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
| Tardive dyskinesia | Disc. AE | 64 mg 1 times / day multiple, oral Recommended Dose: 64 mg, 1 times / day Route: oral Route: multiple Dose: 64 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
| Neuroleptic malignant syndrome | Disc. AE | 64 mg 1 times / day multiple, oral Recommended Dose: 64 mg, 1 times / day Route: oral Route: multiple Dose: 64 mg, 1 times / day Sources: |
unhealthy Health Status: unhealthy Sources: |
| Neuroleptic malignant syndrome | Disc. AE | 20 mg single, intramuscular Studied dose Dose: 20 mg Route: intramuscular Route: single Dose: 20 mg Sources: |
unhealthy |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/10460810/ Page: abstract |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/10460810/ Page: abstract |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/10460810/ Page: abstract |
no | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/10460810/ Page: abstract |
yes [IC50 1.5 uM] | |||
Page: abstract |
yes [IC50 38.2 uM] | |||
Sources: https://dmd.aspetjournals.org/content/44/3/378.short Page: 42.0 |
yes [IC50 66.2 uM] | |||
Sources: https://pubmed.ncbi.nlm.nih.gov/10460810/ Page: abstract |
yes [Ki 65.1 uM] | |||
Sources: https://iv.iiarjournals.org/content/23/6/943.short Page: 945.0 |
yes | |||
Page: 962.0 |
yes |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Page: 961.0 |
yes | |||
Page: 510.0 |
yes | |||
Page: 961.0 |
yes | |||
Page: 961.0 |
yes |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
Page: 1033.0 |
||||
Page: abstract |
PubMed
| Title | Date | PubMed |
|---|---|---|
| The bucco-linguo-masticatory syndrome as a side-effect of neuroleptics therapy. | 1967 |
|
| Phenothiazines in early labour. | 1967 Feb 11 |
|
| Idiosyncratic responses to phenothiazines. | 1972 Jan 22 |
|
| The mechanism of the potentiating effect of antidepressant drugs on the protective influenc oe of diphenhydramine in experimental catatonia. The role of histamine. | 1974 |
|
| Letter: Side-effects of perphenazine. | 1975 Jun 21 |
|
| Drug-induced dystonia. | 1975 May |
|
| Drug-induced anaphylaxis, convulsions, deafness, and extrapyramidal symptoms. | 1977 Mar 12 |
|
| Electrophysiologic studies of perphenazine and protriptyline in a patient with psychotropic drug-induced ventricular fibrillation. | 1979 Aug |
|
| Actions of clonidine on convulsions and behaviour. | 1981 Jul |
|
| Unique sensitivity of Hb Zürich to oxidative injury by phenazopyridine: reversal of the effects by elevating carboxyhemoglobin levels in vivo and in vitro. | 1983 Jun |
|
| Effect of different neuroleptics in tardive dyskinesia and parkinsonism. A video-controlled multicenter study with chlorprothixene, perphenazine, haloperidol and haloperidol + biperiden. Nordic Dyskinesia Study Group. | 1986 |
|
| Tourette-like syndrome following low dose short-term neuroleptic treatment. | 1986 May |
|
| Zuclopenthixol and perphenazine in patients with acute psychotic states. A double-blind multicentre study. | 1987 Jul |
|
| Neurologic approach to drug-induced movement disorders: a study of 125 patients. | 1990 May |
|
| D1/D2 dopamine and N-methyl-D-aspartate (NMDA) receptor participation in experimental catalepsy in rats. | 1992 |
|
| Association of plasma homovanillic acid with behavioral symptoms in patients diagnosed with dementia: a preliminary report. | 1997 Dec 1 |
|
| Olanzapine use in women with antipsychotic-induced hyperprolactinemia. | 1998 Oct |
|
| Acquired aplastic anemia secondary to perphenazine. | 1999 Autumn |
|
| Perphenazine-induced hiccups. | 1999 Mar |
|
| [Diabetes mellitus after treatment with clozapine]. | 2000 Feb 26 |
|
| Antipsychotic-induced extrapyramidal syndromes. Risperidone compared with low- and high-potency conventional antipsychotic drugs. | 2001 Jul |
|
| Quercetin potentiates L-Dopa reversal of drug-induced catalepsy in rats: possible COMT/MAO inhibition. | 2003 Jun |
|
| H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. | 2003 Mar |
|
| An unexpected increase of troponin I after perphenazine depot injection. | 2004 Feb |
|
| Stable expression of constitutively activated mutant h5HT6 and h5HT7 serotonin receptors: inverse agonist activity of antipsychotic drugs. | 2005 May |
|
| Clinical characteristics and psychopathological profile of patients with vulvodynia: an observational and descriptive study. | 2008 |
|
| Identification of selected therapeutic agents as inhibitors of carboxylesterase 1: potential sources of metabolic drug interactions. | 2010 Apr 11 |
|
| Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting. | 2010 Dec |
|
| A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle. | 2010 Feb 23 |
|
| Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2. | 2011 Jul 14 |
|
| Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine. | 2014 Jun |
Patents
Sample Use Guides
Moderately disturbed nonhospitalized patients with schizophrenia: 4 to 8 mg t.i.d. initially; reduce as soon as possible to minimum effective dosage. Hospitalized patients with schizophrenia: 8 to 16 mg b.i.d. to q.i.d.; avoid dosages in excess of 64 mg daily. Severe nausea and vomiting in adults: 8 to 16 mg daily in divided doses; 24 mg occasionally may be necessary; early dosage reduction is desirable.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12043843
Perphenazine (10-100 microM) was administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry-NB) were determined. Neuroblastoma: perphenazine decreased viability by 87%.
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| Classification Tree | Code System | Code | ||
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NDF-RT |
N0000175746
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WHO-VATC |
QN05AB03
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LIVERTOX |
NBK548366
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NCI_THESAURUS |
C29710
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NDF-RT |
N0000007544
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N0000007544
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N0000007544
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WHO-ATC |
N05AB03
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8076
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637
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SUB09736MIG
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CHEMBL567
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DTXSID1023441
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DB00850
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D010546
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FTA7XXY4EZ
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PERPHENAZINE
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C29355
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8028
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2113
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4748
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100000092394
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58-39-9
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200-381-5
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m8567
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3379
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Perphenazine
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209
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ACTIVE MOIETY
METABOLITE (PARENT)
METABOLITE (PARENT)
METABOLITE (PARENT)
SALT/SOLVATE (PARENT)
SALT/SOLVATE (PARENT)