CLOZAPINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C18H19ClN4
Molecular Weight	326.823
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CC1)C2=NC3=CC(Cl)=CC=C3NC4=CC=CC=C24

InChI

InChIKey=QZUDBNBUXVUHMW-UHFFFAOYSA-N

InChI=1S/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3

HIDE SMILES / InChI

Molecular Formula	C18H19ClN4
Molecular Weight	326.823
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019758s074lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/10372606

Clozapine was discovered in 1958 by an anesthetist and now it is used for the treatment of schizophrenia. Although the exact mechanism of its action is unknown, the effect of clozapine on schizophrenia is associated with inhibition of dopamine D2 and serotonin 2A receptors.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dopamine D2 receptor 311 Target ID: CHEMBL217 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019758s074lbl.pdf	Antagonist 2849		160.0 nM [Ki]
Serotonin 2a (5-HT2a) receptor 237 Target ID: CHEMBL224 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019758s074lbl.pdf	Antagonist 2849		5.4 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Treatment-resistant schizophrenia 2 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/019758s074lbl.pdf	Primary		Approved 8583	CLOZARIL Approved Use Clozaril is an atypical antipsychotic indicated for: Treatment-resistant schizophrenia. Launch Date 1989

C_max

Value	Dose	Co-administered	Analyte	Population
319 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019758s073lbl.pdf	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLOZAPINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN
98 nM EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10606838	12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLOZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
1348 nM × h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10606838	12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLOZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019758s073lbl.pdf	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLOZAPINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN
18.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/10606838	12.5 mg single, oral dose: 12.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLOZAPINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
3% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/019758s073lbl.pdf	100 mg 2 times / day steady-state, oral dose: 100 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLOZAPINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
289 mg 1 times / day multiple, oral Recommended Dose: 289 mg, 1 times / day Route: oral Route: multiple Dose: 289 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10831480/	unhealthy, 41 Health Status: unhealthy Age Group: 41 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/10831480/	Other AEs: Sedation, Salivation... Other AEs: Sedation (14 patients) Salivation (6 patients) Constipation (6 patients) Nausea and vomiting (5 patients) Dizziness (4 patients) Fever (4 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/10831480/
296 mg 1 times / day multiple, oral Recommended Dose: 296 mg, 1 times / day Route: oral Route: multiple Dose: 296 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20586532/	unhealthy, 74.2 years (range: 65-89 years) Health Status: unhealthy Age Group: 74.2 years (range: 65-89 years) Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/20586532/	Disc. AE: Orthostatic hypotension, Sedation... Other AEs: Sedation, Hypersalivation... AEs leading to discontinuation/dose reduction: Orthostatic hypotension (13 patients) Sedation (1 patient) Dysphagia (1 patient) Fever (2 patients) Tachycardia (2 patients) Myocarditis (1 patient) Leukopenia (3 patients) Parkinsonism (1 patient) Myocardial infarction (3 patients) Ataxia (1 patient) Cardiomyopathy (1 patient) Other AEs: Sedation (28 patients) Hypersalivation (25 patients) Constipation (16 patients) Weight gain (8 patients) Leukopenia (4 patients) Tachycardia (3 patients) Leukopenia (2 patients) Seizure (2 patients) Dysphagia (1 patient) Fever (1 patient) Fatigue (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/20586532/
450 mg 1 times / day multiple, oral Recommended Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/14971863/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/14971863/	Other AEs: Dry mouth, Urinary hesitancy... Other AEs: Dry mouth (20%) Urinary hesitancy (10%) Constipation (60%) Nausea (60%) Dyspepsia (70%) Headache (40%) Somnolence (100%) Lethargy (90%) Myoclonus (30%) Stuttering (20%) Sialorrhea (80%) Sweating (50%) Urinary frequency (40%) Dysphagia (20%) Orthostatic hypotension (10%) Dizziness (60%) Increased appetite (50%) Sources: https://pubmed.ncbi.nlm.nih.gov/14971863/
900 mg 1 times / day multiple, oral Recommended Dose: 900 mg, 1 times / day Route: oral Route: multiple Dose: 900 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3046553/	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/3046553/	Other AEs: Drowsiness, Tachycardia... Other AEs: Drowsiness (21%) Tachycardia (17%) Constipation (16%) Dizziness (14%) Hypotension (13%) Hyperthermia (13%) Salivation (13%) Hypertension (12%) Headache (10%) Nausea and vomiting (10%) Dry mouth (5%) Sources: https://pubmed.ncbi.nlm.nih.gov/3046553/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946	substrate 1193 inhibitor 2438	substrate 1388 inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 CYP2C19 2057 BCRP 910 P-gp 1741 OATP1B1 1079 OATP1B3 961	UGT1A4 399 CYP1A1 389 CYP1A2 1197 CYP3A5 446 CYP2C8 810 CYP2C19 1119 CYP2E1 729 FMO3 77 UGT1A1 479 P-gp 2052 OCT1 393 OCT3 92 OCTN1 55 OCTN2 59 OATP1B1 503 OATP1B3 435

Drug as perpetrator

Target	Modality	Activity
OATP1B1 1095	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OATP1B3 970	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
BCRP 985	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/18834354/	yes [IC50 42 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/8866916/	yes [Ki 19 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/8866916/	yes [Ki 31 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/8866916/	yes [Ki 69 uM]
CYP3A 317	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/8866916/	yes [Ki 99 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/22525746/ \| https://pubmed.ncbi.nlm.nih.gov/15961125/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1197	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf	major	yes (co-administration study) Comment: co-administration with fluvoxamin lead to 3x increase in clozapine Cmin Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf
CYP2C19 1119	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/	minor
CYP2C9 1193	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \|https://pubmed.ncbi.nlm.nih.gov/17504220/	minor
CYP2D6 1388	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/23297297/ \| https://pubmed.ncbi.nlm.nih.gov/1545398/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf	minor
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/23297297/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf	minor	weak (co-administration study) Comment: co-administration studies indicate modest (<2x) increase in clozapine exposure when co-administered with CYP3A4 inhibitors Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/ \| https://pubmed.ncbi.nlm.nih.gov/23297297/ \| https://pubmed.ncbi.nlm.nih.gov/17504220/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019758s084lbl.pdf
CYP1A1 389	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/	no
OATP1B1 503	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OATP1B3 435	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OCT1 393	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OCT3 92	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OCTN1 55	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
OCTN2 59	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/29944835/	no
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/28272498/	no
CYP2C8 810	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/	yes
CYP2E1 729	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/	yes
CYP3A5 446	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/	yes
FMO3 77	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/9840430/	yes
UGT1A4 399	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/15708967/	yes
UGT1A1 479	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22565219/	yes	yes (pharmacogenomic study) Comment: UGT1A128 and UGT1A43 alleles contribute significantly to inter-individual variability in CLZ and dmCLZ metabolism Sources: https://pubmed.ncbi.nlm.nih.gov/22565219/

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://pubmed.ncbi.nlm.nih.gov/16633353/ \| https://pubmed.ncbi.nlm.nih.gov/12503253/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3766	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3766
ChemicalBook	CB7776111	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7776111
eMolecules	536309	https://www.emolecules.com/cgi-bin/more?vid=536309
MolPort	MolPort-001-728-041	https://www.molport.com/shop/molecule-link/MolPort-001-728-041
Selleck Chemicals	Clozapine(Clozaril)	http://www.selleckchem.com/products/Clozapine(Clozaril).html
ZINC	ZINC000019796155	http://zinc15.docking.org/substances/ZINC000019796155

PubMed

Title	Date	PubMed
Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics.	2001-04	11222923
Electroconvulsive therapy in rehabilitation: the Hong Kong experience.	2001-03	11239096
5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release.	2001-03	11238736
Atypical antipsychotics and hyperglycaemia.	2001-03	11236071
Clozapine and pulmonary embolus.	2001-03	11230003
Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis.	2001-03	11229973
Pharmacological characterization of locomotor sensitization induced by chronic phencyclidine administration.	2001-03	11181923
Cloning, expression, and pharmacological characterization of a novel human histamine receptor.	2001-03	11179436
Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow.	2001-03	11179434
Double activity imaging reveals distinct cellular targets of haloperidol, clozapine and dopamine D(3) receptor selective RGH-1756.	2001-03	11166331
Haloperidol and clozapine increase neural activity in the rat prefrontal cortex.	2001-02-09	11165445
New onset diabetes and atypical antipsychotics.	2001-02	11226809
Is generic really the same?	2001-02	11216062
Possible serotonin syndrome associated with clomipramine after withdrawal of clozapine.	2001-02	11215836
Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.	2001-02	11199953
Mitchell B. Balter Award. Human leukocyte antigen-A1 predicts a good therapeutic response to clozapine with a low risk of agranulocytosis in patients with schizophrenia.	2001-02	11199946
FosB in rat striatum: normal regional distribution and enhanced expression after 6-month haloperidol administration.	2001-02	11180499
Uncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptors alter the mRNA expression of proteins associated with the NMDA receptor complex.	2001-02	11169168
Clozapine increases apolipoprotein D expression in rodent brain: towards a mechanism for neuroleptic pharmacotherapy.	2001-02	11158250
Subspecialty training in schizophrenia.	2001-02	11157129
Increased dopamine d(2) receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine.	2001-02	11156818
Clozapine-associated reduction in arrest rates of psychotic patients with criminal histories.	2001-02	11156810
Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum.	2001-01-26	11165224
Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment.	2001-01-22	11201068
Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia.	2001-01-15	11163544
Risperidone-associated hyperprolactinemia.	2001-01-13	11155212
Myotoxicity and neurotoxicity during clozapine treatment.	2001-01-12	11154096
A proposed pathological model in the hippocampus of subjects with schizophrenia.	2001-01-12	11153541
Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.	2001-01-01	11163780
Bodyweight gain with atypical antipsychotics. A comparative review.	2001-01	11219487
Clozapine for the treatment of drug-induced psychosis in Parkinson's disease: results of the 12 week open label extension in the PSYCLOPS trial.	2001-01	11215574
Olanzapine-induced leukopenia with human leukocyte antigen profiling.	2001-01	11195261
Pharmacokinetic-pharmacodynamic modelling in the early development phase of anti-psychotics: a comparison of the effects of clozapine, S 16924 and S 18327 in the EEG model in rats.	2001-01	11156572
Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-jewish caucasian sample.	2001-01	11146763
Trimethoprim-sulfamethoxazole and clozapine.	2001-01	11141546
Clozapine therapy for a patient with a history of Hodgkin's disease.	2001-01	11141545
The clozapine access project.	2001-01	11141542
Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat.	2001-01	11106876
The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics.	2001-01	11106875
Antipsychotic medications and the elderly: effects on cognition and implications for use.	2001	11232738
Olanzapine: an updated review of its use in the management of schizophrenia.	2001	11217867
Effects of systemic injections of dopaminergic agents on the habituation of rats submitted to an open field test.	2001	11174051
Evidence for an association between polymorphism in the serotonin-2A receptor variant (102T/C) and increment of N100 amplitude in schizophrenics treated with clozapine.	2001	11174050
Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia.	2001	11160792
Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats.	2001	11114408
Reemergence of tardive dyskinesia after discontinuation of clozapine treatment.	2000-12-15	11120422
Panic disorder associated with clozapine.	2000-12	11097983
Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia.	2000-11	11151749
A case of pharmacokinetic interference in comedication of clozapine and valproic acid.	2000-11	11147932
Hyperglycemia, hyperlipemia, and periodic paralysis: a case report of new side effects of clozapine.	2000-11	11125862

Patents

Sample Use Guides

In Vivo Use Guide

Start with 12.5 mg once daily or twice daily, then increase the total daily dosage in increments of 25 mg to 50 mg per day (if well-tolerated) in order to reach 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks.

Route of Administration: Oral

In Vitro Use Guide

The effects of antipsychotic medication on the energy metabolism of OLN-93 cells were analyzed by adding a vehicle (0.01% HCl, same dissolving solution used to solubilize the antipsychotics), 1 or 10 ug/ml of clozapine to the cell culture for 6 or 24 h.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 17:47:22 GMT 2025` Edited by `admin` on `Mon Mar 31 17:47:22 GMT 2025`
Record UNII	J60AR2IKIC
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CLOZAPINE RESOLUTION MIXTURE

Preferred Name

English

CLOZAPINE

Official Name

English

CLOZAPINE [JAN]

Common Name

English

LEPONEX

Brand Name

English

8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine

Systematic Name

English

CLOZAPINE [USP-RS]

Common Name

English

CLOZAPINE [MI]

Common Name

English

CLOZAPINE (CLOZARIL) [VANDF]

Common Name

English

CLOZAPINE (FAZACLO) [VANDF]

Common Name

English

CLOZAPINE [USAN]

Common Name

English

CLOZAPINE RESOLUTION MIXTURE [USP-RS]

Common Name

English

CLOZARIL

Brand Name

English

CLOZAPINE [USP MONOGRAPH]

Common Name

English

CLOZAPINE [HSDB]

Common Name

English

HF-1854

Code

English

FAZACLO

Brand Name

English

clozapine [INN]

Common Name

English

CLOZAPINE (VERSACLOZ) [VANDF]

Common Name

English

CLOZAPINE [EP MONOGRAPH]

Common Name

English

Clozapine [WHO-DD]

Common Name

English

CLOZAPINE (IVAX) [VANDF]

Common Name

English

5H-DIBENZO(B,E)(1,4)DIAZEPINE, 8-CHLORO-11-(4-METHYL-1-PIPERAZINYL)-

Systematic Name

English

NSC-757429

Code

English

CLOZAPINE (CARACO) [VANDF]

Common Name

English

HF 1854

Code

English

CLOZAPINE (MYLAN) [VANDF]

Common Name

English

CLOZAPINE [VANDF]

Common Name

English

CLOZAPINE (UDL) [VANDF]

Common Name

English

CLOZAPINE (TEVA) [VANDF]

Common Name

English

CLOZAPINE [MART.]

Common Name

English

CLOZAPINE [ORANGE BOOK]

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

357411