Identification

Summary

Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients.

Brand Names
Clozaril, Fazaclo, Versacloz
Generic Name
Clozapine
DrugBank Accession Number
DB00363
Background

Clozapine is a tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent.23 Clozapine displays affinity to various neuroreceptors with a particularly low affinity to the dopamine receptors, thus breaking the mold of first-generation antipsychotics and deeming it "atypical".26. This low affinity to dopamine receptors results in fewer extrapyramidal side effects, especially tardive dyskinesia.21 However, its promiscuity toward the muscarinic and adrenergic receptors can result in other side effects, notably gastrointestinal hypomotility and orthostatic hypotension. 27,8. Despite its effectiveness in treating both positive and negative symptoms of schizophrenia, clozapine was briefly removed from the market in various jurisdictions in 1970 due to severe agranulocytosis.24,25 However, continued evidence of its effectiveness led to clozapine's eventual reintroduction, although with a reluctance to prescribe it.25

Clozapine was approved by the FDA in 1989 for treatment-resistant schizophrenia under the brand CLOZARIL.27 Due to its severe adverse effects profile, clozapine is only available through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program.27

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 326.823
Monoisotopic: 326.129824335
Chemical Formula
C18H19ClN4
Synonyms
  • Clozapin
  • Clozapina
  • Clozapine
  • Clozapinum
External IDs
  • HF 1854
  • HF-1854
  • LX 100-129
  • W 108

Pharmacology

Indication

Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.27

Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death.27

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia.22 Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors, research have shown that clozapine can act on various types of receptors.21

Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use.27 Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection.8,27 Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils.6 Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs.27 Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program.7 These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged.27

Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients.5 Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine.27

Mechanism of action

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5-HT2A) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors.27

Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM).27

Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects.18 Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug.19 Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.20

TargetActionsOrganism
UDopamine D1 receptor
antagonist
Humans
ADopamine D2 receptor
antagonist
Humans
UDopamine D3 receptor
antagonist
Humans
UDopamine D4 receptor
antagonist
Humans
UDopamine D5 receptor
binder
Humans
U5-hydroxytryptamine receptor 1A
antagonist
Humans
U5-hydroxytryptamine receptor 1B
antagonist
Humans
U5-hydroxytryptamine receptor 1D
antagonist
Humans
U5-hydroxytryptamine receptor 1E
antagonist
Humans
A5-hydroxytryptamine receptor 2A
antagonist
Humans
U5-hydroxytryptamine receptor 3A
antagonist
Humans
U5-hydroxytryptamine receptor 2C
antagonist
Humans
U5-hydroxytryptamine receptor 6
antagonist
Humans
U5-hydroxytryptamine receptor 7
antagonist
Humans
NAlpha-2C adrenergic receptor
antagonist
Humans
UHistamine H1 receptor
antagonist
Humans
NHistamine H4 receptor
antagonist
Humans
UAlpha-1A adrenergic receptor
antagonist
Humans
NAlpha-1B adrenergic receptor
antagonist
Humans
UAlpha-2A adrenergic receptor
antagonist
Humans
NAlpha-2B adrenergic receptor
antagonist
Humans
UMuscarinic acetylcholine receptor M1
partial agonist
Humans
UMuscarinic acetylcholine receptor M2
partial agonist
Humans
UMuscarinic acetylcholine receptor M3
antagonist
Humans
UMuscarinic acetylcholine receptor M4
partial agonist
Humans
UMuscarinic acetylcholine receptor M5
antagonist
Humans
UNeuron-specific vesicular protein calcyon
unknown
Humans
UGlutathione S-transferase PNot AvailableHumans
UGamma-aminobutyric acid type B receptor subunit 1
positive modulator
Humans
UGamma-aminobutyric acid type B receptor subunit 2
positive modulator
Humans
UGamma-aminobutyric acid receptor subunit alpha-1
antagonist
Humans
UGamma-aminobutyric acid receptor subunit beta-1
antagonist
Humans
UGamma-aminobutyric acid receptor subunit gamma-1
antagonist
Humans
Absorption

In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing.27

Volume of distribution

The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L).9,10,11,13,12

Protein binding

Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important.27

Metabolism

Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.27

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Route of elimination

Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.27

Half-life

The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing.27

A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics.27

Clearance

The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h).10,12,14,15,16,17

Adverse Effects
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Toxicity

There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed.27

Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization.27

The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement.27

No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis.27

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3---(T;T)TT alleleADR Directly StudiedPatients with this genotype have increased weight gain with clozapine.Details
Cytochrome P450 2D6CYP2D6*3Not AvailableC alleleEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableC alleleEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*68BNot AvailableSimilar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCEffect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer.Details

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of adverse effects can be increased when 1,2-Benzodiazepine is combined with Clozapine.
AbacavirClozapine may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Clozapine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Clozapine can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Clozapine.
AbirateroneThe serum concentration of Clozapine can be increased when it is combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Clozapine.
AcalabrutinibThe serum concentration of Clozapine can be increased when it is combined with Acalabrutinib.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Clozapine.
AcebutololThe serum concentration of Clozapine can be increased when it is combined with Acebutolol.
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Food Interactions
  • Avoid alcohol. Alcohol is a predisposing risk factor for seizure in combination with clozapine.
  • Exercise caution with St. John's Wort. This herb induces both CYP3A4 and CYP1A2 metabolism and may reduce clozapine serum levels.
  • Limit caffeine intake. Caffeine may reduce clozapine metabolism.
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Clozapine hydrochloride80862U56A354241-01-9ARWPDHKDEREYEE-UHFFFAOYSA-N
Product Images
International/Other Brands
Azaleptine (Arpimed) / Cloment (Pharmaplan) / Clonex (Adeka) / Clopin (East West) / Clopine (Douglas) / Clopsine (Psicofarma) / Clorazem (Remedica) / Lanolept (Lannacher) / Lapenax (Novartis) / Leponex (Novartis) / Lodux (Rider) / Lozapin (Torrent) / Luften (Pharos) / Mezapin (Panbiotic) / Refract (Crescent) / Refraxol (AC Farma) / Sensipin (Beximco) / Sequax (Ivax) / Sizopin (Sun) / Sizopril (Meprofarm) / Syclop (Brown & Burk Phils) / Syzopin (Psyco Remedies) / Tanyl (Novamed) / Uspen (Yu Sheng) / Zapen (Psipharma) / Zapenia (Incepta) / Zapine (Taiwan Biotech) / Ziproc (Torrent) / Zopin (Psychotropics India)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ClozapineTablet25 mg/1OralSandoz Inc.2016-05-062021-06-30US flag
ClozapineTablet100 mg/1OralHeartwood Pharma2019-04-15Not applicableUS flag
ClozapineTablet200 mg/1OralHeartwood Pharma2019-07-30Not applicableUS flag
ClozapineTablet100 mg/1OralSandoz Inc.2016-05-062021-03-31US flag
ClozapineTablet25 mg/1OralHeartwood Pharma2019-04-15Not applicableUS flag
ClozapineTablet100 mg/1OralTEVA PHARMACEUTICALS USA2008-03-172008-03-17US flag
ClozapineTablet50 mg/1OralHeartwood Pharma2019-07-30Not applicableUS flag
Clozapine TabletsTablet25 mgOralInnomar Strategies Inc.Not applicableNot applicableCanada flag
Clozapine TabletsTablet100 mgOralInnomar Strategies Inc.Not applicableNot applicableCanada flag
ClozarilTablet200 mg/1OralHLS Therapeutics (USA), Inc.2019-12-17Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Aa-clozapineTablet200 mgOralAa Pharma Inc2017-02-27Not applicableCanada flag
Aa-clozapineTablet25 mgOralAa Pharma Inc2004-01-27Not applicableCanada flag
Aa-clozapineTablet50 mgOralAa Pharma Inc2017-02-27Not applicableCanada flag
Aa-clozapineTablet100 mgOralAa Pharma Inc2004-01-27Not applicableCanada flag
Auro-clozapineTablet50 mgOralAuro Pharma IncNot applicableNot applicableCanada flag
Auro-clozapineTablet200 mgOralAuro Pharma IncNot applicableNot applicableCanada flag
Auro-clozapineTablet25 mgOralAuro Pharma IncNot applicableNot applicableCanada flag
Auro-clozapineTablet100 mgOralAuro Pharma IncNot applicableNot applicableCanada flag
ClozapineTablet, orally disintegrating150 mg/1OralTeva Pharmaceuticals USA Inc2015-05-052022-08-31US flag
ClozapineTablet25 mg/1OralMayne Pharma2016-08-032021-04-30US flag

Categories

ATC Codes
N05AH02 — Clozapine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dibenzodiazepines. These are compounds containing a dibenzodiazepine moiety, which consists of two benzene connected by diazepine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzodiazepines
Sub Class
Dibenzodiazepines
Direct Parent
Dibenzodiazepines
Alternative Parents
1,4-benzodiazepines / N-methylpiperazines / Imidolactams / Benzenoids / Aryl chlorides / Trialkylamines / Secondary amines / Propargyl-type 1,3-dipolar organic compounds / Carboxamidines / Azacyclic compounds
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Substituents
1,4-benzodiazepine / 1,4-diazinane / Amidine / Amine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carboxylic acid amidine
show 16 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
N-arylpiperazine, organochlorine compound, N-methylpiperazine, benzodiazepine (CHEBI:3766)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
J60AR2IKIC
CAS number
5786-21-0
InChI Key
QZUDBNBUXVUHMW-UHFFFAOYSA-N
InChI
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
IUPAC Name
6-chloro-10-(4-methylpiperazin-1-yl)-2,9-diazatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,9,11,13-heptaene
SMILES
CN1CCN(CC1)C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12

References

Synthesis Reference

Schmutz, J. and Hunziker, F.; US. Patent 3,539,573; November 10, 1970 .

US3539573
General References
  1. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA: Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993 Jul 15;329(3):162-7. [Article]
  2. Vaddadi KS, Soosai E, Vaddadi G: Low blood selenium concentrations in schizophrenic patients on clozapine. Br J Clin Pharmacol. 2003 Mar;55(3):307-9. [Article]
  3. Naheed M, Green B: Focus on clozapine. Curr Med Res Opin. 2001;17(3):223-9. [Article]
  4. Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW: Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry. 1999 Jan;60(1):36-40. [Article]
  5. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ: A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust N Z J Psychiatry. 2011 Jun;45(6):458-65. doi: 10.3109/00048674.2011.572852. Epub 2011 Apr 27. [Article]
  6. Wicinski M, Weclewicz MM: Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring. Curr Opin Hematol. 2018 Jan;25(1):22-28. doi: 10.1097/MOH.0000000000000391. [Article]
  7. Borrelli EP, Lee EY, Caffrey AR: Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program. Ment Health Clin. 2020 May 7;10(3):70-75. doi: 10.9740/mhc.2020.05.070. eCollection 2020 May. [Article]
  8. Kar N, Barreto S, Chandavarkar R: Clozapine Monitoring in Clinical Practice: Beyond the Mandatory Requirement. Clin Psychopharmacol Neurosci. 2016 Nov 30;14(4):323-329. doi: 10.9758/cpn.2016.14.4.323. [Article]
  9. Guitton C, Abbar M, Kinowski JM, Chabrand P, Bressolle F: Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol. 1998 Dec;18(6):470-6. doi: 10.1097/00004714-199812000-00010. [Article]
  10. Jerling M, Merle Y, Mentre F, Mallet A: Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol. 1997 Nov;44(5):447-53. doi: 10.1046/j.1365-2125.1997.t01-1-00606.x. [Article]
  11. Dailly E, Urien S, Chanut E, Claudel B, Guerra N, Femandez C, Jolliet P, Bourin M: Evidence from a population pharmacokinetics analysis for a major effect of CYP1A2 activity on inter- and intraindividual variations of clozapine clearance. Prog Neuropsychopharmacol Biol Psychiatry. 2002 May;26(4):699-703. doi: 10.1016/s0278-5846(01)00320-7. [Article]
  12. Doude van Troostwijk LJ, Koopmans RP, Vermeulen HD, Guchelaar HJ: CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. Eur J Pharm Sci. 2003 Dec;20(4-5):451-7. [Article]
  13. Li LJ, Shang DW, Li WB, Guo W, Wang XP, Ren YP, Li AN, Fu PX, Ji SM, Lu W, Wang CY: Population pharmacokinetics of clozapine and its primary metabolite norclozapine in Chinese patients with schizophrenia. Acta Pharmacol Sin. 2012 Nov;33(11):1409-16. doi: 10.1038/aps.2012.71. Epub 2012 Jul 23. [Article]
  14. Ng W, Uchida H, Ismail Z, Mamo DC, Rajji TK, Remington G, Sproule B, Pollock BG, Mulsant BH, Bies RR: Clozapine exposure and the impact of smoking and gender: a population pharmacokinetic study. Ther Drug Monit. 2009 Jun;31(3):360-6. doi: 10.1097/FTD.0b013e31819c7037. [Article]
  15. Ismail Z, Wessels AM, Uchida H, Ng W, Mamo DC, Rajji TK, Pollock BG, Mulsant BH, Bies RR: Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia. Am J Geriatr Psychiatry. 2012 Jan;20(1):53-60. doi: 10.1097/JGP.0b013e3182118318. [Article]
  16. Li AN, Dong F, He JL, Shang DW, Guo W, Li WB, Lu W, Wang CY: The Elimination Rate after Clozapine Overdose in Chinese Schizophrenia Patients: A Population Pharmacokinetics Model Study. Pharmacopsychiatry. 2015 Jul;48(4-5):150-5. doi: 10.1055/s-0035-1554672. Epub 2015 Jun 16. [Article]
  17. Olmos I, Ibarra M, Vazquez M, Maldonado C, Fagiolino P, Giachetto G: Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia. Biomed Res Int. 2019 Mar 6;2019:3163502. doi: 10.1155/2019/3163502. eCollection 2019. [Article]
  18. Li Z, Huang M, Ichikawa J, Dai J, Meltzer HY: N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology. 2005 Nov;30(11):1986-95. doi: 10.1038/sj.npp.1300768. [Article]
  19. Fang F, Sun H, Wang Z, Ren M, Calabrese JR, Gao K: Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management. CNS Drugs. 2016 Sep;30(9):845-67. doi: 10.1007/s40263-016-0352-5. [Article]
  20. Tanzer TD, Brouard T, Pra SD, Warren N, Barras M, Kisely S, Brooks E, Siskind D: Treatment strategies for clozapine-induced hypotension: a systematic review. Ther Adv Psychopharmacol. 2022 May 24;12:20451253221092931. doi: 10.1177/20451253221092931. eCollection 2022. [Article]
  21. Li P, Snyder GL, Vanover KE: Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future. Curr Top Med Chem. 2016;16(29):3385-3403. doi: 10.2174/1568026616666160608084834. [Article]
  22. Keating D, McWilliams S, Schneider I, Hynes C, Cousins G, Strawbridge J, Clarke M: Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017 Jan 6;7(1):e013881. doi: 10.1136/bmjopen-2016-013881. [Article]
  23. Iqbal MM, Rahman A, Husain Z, Mahmud SZ, Ryan WG, Feldman JM: Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003 Mar;15(1):33-48. doi: 10.1023/a:1023228626309. [Article]
  24. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A, Carpenter WT Jr: Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994 Jan;151(1):20-6. doi: 10.1176/ajp.151.1.20. [Article]
  25. Siskind D, McCartney L, Goldschlager R, Kisely S: Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016 Nov;209(5):385-392. doi: 10.1192/bjp.bp.115.177261. Epub 2016 Jul 7. [Article]
  26. Khokhar JY, Henricks AM, Sullivan EDK, Green AI: Unique Effects of Clozapine: A Pharmacological Perspective. Adv Pharmacol. 2018;82:137-162. doi: 10.1016/bs.apha.2017.09.009. Epub 2018 Jan 12. [Article]
  27. FDA Approved Drug Products: CLOZARIL® (clozapine) tablets, for oral use [Link]
  28. DailyMed Label: CLOZARI (clozapine) tablets, for oral use [Link]
Human Metabolome Database
HMDB0014507
KEGG Drug
D00283
KEGG Compound
C06924
PubChem Compound
2818
PubChem Substance
46506474
ChemSpider
10442628
BindingDB
50001884
RxNav
2626
ChEBI
3766
ChEMBL
CHEMBL42
ZINC
ZINC000019796155
Therapeutic Targets Database
DAP000029
PharmGKB
PA449061
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Clozapine
FDA label
Download (89.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceSchizoaffective Disorders / Schizophrenia1
4CompletedHealth Services ResearchSchizophrenia1
4CompletedTreatmentCannabis Abuse / Cannabis Dependence / Dual Diagnosis / Schizophrenia1
4CompletedTreatmentCannabis Abuse / Dual Diagnosis / Psychosis / Schizoaffective Disorders / Schizophrenia1
4CompletedTreatmentPanic Disorder1
4CompletedTreatmentPsychosis / Schizophrenia1
4CompletedTreatmentPsychosis / Schizophrenia / Schizophrenia, Childhood1
4CompletedTreatmentSchizoaffective Disorders / Schizophrenia2
4CompletedTreatmentSchizoaffective Disorders / Schizophrenia / Schizophreniform Disorders1
4CompletedTreatmentSchizophrenia8

Pharmacoeconomics

Manufacturers
  • Azur pharma international iii ltd
  • Caraco pharmaceutical laboratories ltd
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mylan pharmaceuticals inc
  • Par pharmaceutical
  • Sandoz inc
  • Novartis pharmaceuticals corp
Packagers
  • Alamo Pharmaceuticals LLC
  • Amerisource Health Services Corp.
  • Avanir Pharmaceuticals
  • AzurPharma Inc.
  • Caraco Pharmaceutical Labs
  • Cardinal Health
  • Cima Laboratories Inc.
  • Heartland Repack Services LLC
  • Ivax Pharmaceuticals
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Neuman Distributors Inc.
  • Novartis AG
  • Novopharm Ltd.
  • Physicians Total Care Inc.
  • Resource Optimization and Innovation LLC
  • Sandhills Packaging Inc.
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
Dosage Forms
FormRouteStrength
SuspensionOral
TabletOral
Tablet, film coatedOral100 mg
Tablet, coatedOral25 mg
TabletOral200 mg/1
TabletOral50 mg/1
Tablet, orally disintegratingOral100 mg/1
Tablet, orally disintegratingOral12.5 mg/1
Tablet, orally disintegratingOral150 mg/1
Tablet, orally disintegratingOral200 mg/1
Tablet, orally disintegratingOral25 mg/1
TabletOral100 mg/1
TabletOral25 mg/1
TabletOral100 MG
TabletOral25 MG
Tablet, film coatedOral105 mg
Tablet, orally disintegratingOral50 mg/1
SuspensionOral50 mg / mL
TabletOral200 mg
TabletOral50 mg
Tablet, film coatedOral25 mg
SuspensionOral50 mg/1mL
Prices
Unit descriptionCostUnit
Fazaclo 100 mg odt6.55USD tablet
Clozapine 200 mg tablet6.32USD tablet
Clozaril 100 mg tablet5.84USD tablet
Clozapine 100 mg tablet3.33USD tablet
Apo-Clozapine 100 mg Tablet2.77USD tablet
Gen-Clozapine 100 mg Tablet2.77USD tablet
Fazaclo 25 mg odt2.4USD tablet
Fazaclo 25 mg tablet2.19USD tablet
Clozaril 25 mg tablet1.96USD tablet
Fazaclo 12.5 mg odt1.79USD tablet
Clozapine 50 mg tablet1.65USD tablet
Clozapine 25 mg tablet1.28USD tablet
Apo-Clozapine 25 mg Tablet0.69USD tablet
Gen-Clozapine 25 mg Tablet0.69USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5178878No1993-01-122010-01-12US flag
US6221392No2001-04-242018-04-09US flag
US6024981No2000-02-152018-04-09US flag
US6106861No2000-08-222017-12-05US flag
US8057811No2011-11-152028-05-01US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)183-184 °CPhysProp
water solubility11.8 mg/LNot Available
logP3.23HANSCH,C ET AL. (1995)
pKa7.5EL TAYAR,N ET AL. (1985)
Predicted Properties
PropertyValueSource
Water Solubility0.186 mg/mLALOGPS
logP3.67ALOGPS
logP3.4Chemaxon
logS-3.2ALOGPS
pKa (Strongest Acidic)15.9Chemaxon
pKa (Strongest Basic)7.35Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area30.87 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity97.36 m3·mol-1Chemaxon
Polarizability35.75 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9904
Blood Brain Barrier+0.9614
Caco-2 permeable+0.6151
P-glycoprotein substrateSubstrate0.8684
P-glycoprotein inhibitor IInhibitor0.6791
P-glycoprotein inhibitor IIInhibitor0.7407
Renal organic cation transporterInhibitor0.8049
CYP450 2C9 substrateNon-substrate0.7509
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateSubstrate0.6088
CYP450 1A2 substrateInhibitor0.5722
CYP450 2C9 inhibitorNon-inhibitor0.9432
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.9137
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.571
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9106
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.0838 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8189
hERG inhibition (predictor II)Inhibitor0.7164
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0090000000-bc2ca4d5a76a5facf897
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0009000000-986bc19f7e7e8602d005
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00b9-0049000000-d6315d4aeb74c251e939
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0090000000-27fd28450826291cc8c6
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0290000000-474b25ea27690471db0f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0970000000-a58015260aaddb4245bd
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0930000000-3ccfd048a34fdb4f594f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0009000000-7df53c42e3b1618bfdec
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0049000000-7522cc8ebf988effc792
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0090000000-bd138be4ae488c201ed3
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0190000000-68c8b78f304c38b7b7b5
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0980000000-a9dd724f32c02059c510
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0006-0930000000-61c0f65f163824ddd594
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0090000000-da747a0572aa2c21683f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-002f-0930000000-614883dbe075268cf23a
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00b9-0298000000-50d2ee0b52827fd1aee3
MS/MS Spectrum - , positiveLC-MS/MSsplash10-00di-2690000000-daaa74a4f85f5e8b5926

Targets

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Details
1. Dopamine D1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name
DRD1
Uniprot ID
P21728
Uniprot Name
D(1A) dopamine receptor
Molecular Weight
49292.765 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Details
2. Dopamine D2 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Green AI, Salomon MS, Brenner MJ, Rawlins K: Treatment of schizophrenia and comorbid substance use disorder. Curr Drug Targets CNS Neurol Disord. 2002 Apr;1(2):129-39. [Article]
  2. Weizman T, Pick CG, Backer MM, Rigai T, Bloch M, Schreiber S: The antinociceptive effect of amisulpride in mice is mediated through opioid mechanisms. Eur J Pharmacol. 2003 Oct 8;478(2-3):155-9. [Article]
  3. Young RM, Lawford BR, Barnes M, Burton SC, Ritchie T, Ward WK, Noble EP: Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele. Br J Psychiatry. 2004 Aug;185:147-51. [Article]
  4. Stonehouse AH, Jones FS: Bromocriptine and clozapine regulate dopamine 2 receptor gene expression in the mouse striatum. J Mol Neurosci. 2005;25(1):29-36. [Article]
  5. Takano A, Suhara T, Kusumi I, Takahashi Y, Asai Y, Yasuno F, Ichimiya T, Inoue M, Sudo Y, Koyama T: Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Jan;30(1):75-81. Epub 2005 Jul 22. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Details
3. Dopamine D3 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
Gene Name
DRD3
Uniprot ID
P35462
Uniprot Name
D(3) dopamine receptor
Molecular Weight
44224.335 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Details
4. Dopamine D4 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Sh3 domain binding
Specific Function
Dopamine receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its activity is mediated by G proteins ...
Gene Name
DRD4
Uniprot ID
P21917
Uniprot Name
D(4) dopamine receptor
Molecular Weight
48359.86 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Zhao AL, Zhao JP, Zhang YH, Xue ZM, Chen JD, Chen XG: Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. Int J Neurosci. 2005 Nov;115(11):1539-47. [Article]
  3. Nakane M, Cowart MD, Hsieh GC, Miller L, Uchic ME, Chang R, Terranova MA, Donnelly-Roberts DL, Namovic MT, Miller TR, Wetter JM, Marsh K, Stewart AO, Brioni JD, Moreland RB: 2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist. Neuropharmacology. 2005 Jul;49(1):112-21. Epub 2005 Apr 1. [Article]
  4. Kuballa G, Nowak P, Labus L, Bortel A, Dabrowska J, Swoboda M, Kwiecinski A, Kostrzewa RM, Brus R: Central effects of nafadotride, a dopamine D3 receptor antagonist, in rats. Comparison with haloperidol and clozapine. Pharmacol Rep. 2005 Mar-Apr;57(2):161-9. [Article]
  5. Glatt SJ, Faraone SV, Tsuang MT: Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis. Biol Psychiatry. 2003 Sep 15;54(6):629-35. [Article]
  6. Patel S, Chapman KL, Marston D, Hutson PH, Ragan CI: Pharmacological and functional characterisation of dopamine D4 receptors in the rat retina. Neuropharmacology. 2003 Jun;44(8):1038-46. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.
Gene Name
DRD5
Uniprot ID
P21918
Uniprot Name
D(1B) dopamine receptor
Molecular Weight
52950.5 Da
References
  1. Li P, Snyder GL, Vanover KE: Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future. Curr Top Med Chem. 2016;16(29):3385-3403. doi: 10.2174/1568026616666160608084834. [Article]
  2. Hwang R, Tiwari AK, Zai CC, Felsky D, Remington E, Wallace T, Tong RP, Souza RP, Oh G, Potkin SG, Lieberman JA, Meltzer HY, Kennedy JL: Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Apr 27;37(1):62-75. doi: 10.1016/j.pnpbp.2011.11.018. Epub 2011 Dec 8. [Article]
  3. Perreault ML, Jones-Tabah J, O'Dowd BF, George SR: A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex. Int J Neuropsychopharmacol. 2013 Mar;16(2):477-83. doi: 10.1017/S1461145712000685. Epub 2012 Jul 25. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Hagino Y, Watanabe M: Effects of clozapine on the efflux of serotonin and dopamine in the rat brain: the role of 5-HT1A receptors. Can J Physiol Pharmacol. 2002 Dec;80(12):1158-66. [Article]
  2. Chou YH, Halldin C, Farde L: Occupancy of 5-HT1A receptors by clozapine in the primate brain: a PET study. Psychopharmacology (Berl). 2003 Mar;166(3):234-40. Epub 2003 Feb 13. [Article]
  3. Newman-Tancredi A, Rivet JM, Cussac D, Touzard M, Chaput C, Marini L, Millan MJ: Comparison of hippocampal G protein activation by 5-HT(1A) receptor agonists and the atypical antipsychotics clozapine and S16924. Naunyn Schmiedebergs Arch Pharmacol. 2003 Sep;368(3):188-99. Epub 2003 Aug 16. [Article]
  4. Zahorodna A, Bobula B, Grzegorzewska M, Tokarski K, Hess G: The influence of repeated administration of clozapine and haloperidol on the effects of the activation of 5-HT(1A), 5-HT(2) and 5-HT(4) receptors in rat frontal cortex. J Physiol Pharmacol. 2004 Jun;55(2):371-9. [Article]
  5. Tomic M, Kundakovic M, Butorovic B, Janac B, Andric D, Roglic G, Ignjatovic D, Kostic-Rajacic S: Pharmacological evaluation of selected arylpiperazines with atypical antipsychotic potential. Bioorg Med Chem Lett. 2004 Aug 16;14(16):4263-6. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1B
Uniprot ID
P28222
Uniprot Name
5-hydroxytryptamine receptor 1B
Molecular Weight
43567.535 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1D
Uniprot ID
P28221
Uniprot Name
5-hydroxytryptamine receptor 1D
Molecular Weight
41906.38 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various alkaloids and psychoactive substances. Ligand binding causes a conformation change that trig...
Gene Name
HTR1E
Uniprot ID
P28566
Uniprot Name
5-hydroxytryptamine receptor 1E
Molecular Weight
41681.57 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Goldstein JM: Quetiapine fumarate (Seroquel): a new atypical antipsychotic. Drugs Today (Barc). 1999 Mar;35(3):193-210. [Article]
  2. McDonald LM, Moran PM, Vythelingum GN, Joseph MH, Stephenson JD, Gray JA: Enhancement of latent inhibition by two 5-HT2A receptor antagonists only when given at both pre-exposure and conditioning. Psychopharmacology (Berl). 2003 Sep;169(3-4):321-31. Epub 2002 Aug 9. [Article]
  3. Broderick PA, Hope O, Okonji C, Rahni DN, Zhou Y: Clozapine and cocaine effects on dopamine and serotonin release in nucleus accumbens during psychostimulant behavior and withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Jan;28(1):157-71. [Article]
  4. Heiser P, Schulte E, Hausmann C, Becker R, Remschmidt H, Krieg JC, Vedder H: Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):297-302. [Article]
  5. Reist C, Mazzanti C, Vu R, Fujimoto K, Goldman D: Inter-relationships of intermediate phenotypes for serotonin function, impulsivity, and a 5-HT2A candidate allele: His452Tyr. Mol Psychiatry. 2004 Sep;9(9):871-8. [Article]
  6. Leysen JE, Janssen PM, Megens AA, Schotte A: Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry. 1994 May;55 Suppl:5-12. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Voltage-gated potassium channel activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gate...
Gene Name
HTR3A
Uniprot ID
P46098
Uniprot Name
5-hydroxytryptamine receptor 3A
Molecular Weight
55279.835 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
References
  1. Sodhi MS, Airey DC, Lambert W, Burnet PW, Harrison PJ, Sanders-Bush E: A rapid new assay to detect RNA editing reveals antipsychotic-induced changes in serotonin-2C transcripts. Mol Pharmacol. 2005 Sep;68(3):711-9. Epub 2005 May 25. [Article]
  2. Navailles S, De Deurwaerdere P, Spampinato U: Clozapine and haloperidol differentially alter the constitutive activity of central serotonin2C receptors in vivo. Biol Psychiatry. 2006 Mar 15;59(6):568-75. Epub 2005 Sep 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
Gene Name
HTR6
Uniprot ID
P50406
Uniprot Name
5-hydroxytryptamine receptor 6
Molecular Weight
46953.625 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
Gene Name
HTR7
Uniprot ID
P34969
Uniprot Name
5-hydroxytryptamine receptor 7
Molecular Weight
53554.43 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Protein homodimerization activity
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Gene Name
ADRA2C
Uniprot ID
P18825
Uniprot Name
Alpha-2C adrenergic receptor
Molecular Weight
49521.585 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Details
16. Histamine H1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Roegge CS, Perraut C, Hao X, Levin ED: Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine. Pharmacol Biochem Behav. 2007 Apr;86(4):686-92. Epub 2007 Feb 22. [Article]
  3. Leysen JE, Janssen PM, Megens AA, Schotte A: Risperidone: a novel antipsychotic with balanced serotonin-dopamine antagonism, receptor occupancy profile, and pharmacologic activity. J Clin Psychiatry. 1994 May;55 Suppl:5-12. [Article]
Details
17. Histamine H4 receptor
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agoni...
Gene Name
HRH4
Uniprot ID
Q9H3N8
Uniprot Name
Histamine H4 receptor
Molecular Weight
44495.375 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Sugata Y, Okano M, Fujiwara T, Matsumoto R, Hattori H, Yamamoto M, Nishibori M, Nishizaki K: Histamine H4 receptor agonists have more activities than H4 agonism in antigen-specific human T-cell responses. Immunology. 2007 Jun;121(2):266-75. Epub 2007 Mar 7. [Article]
  3. Smits RA, Lim HD, Stegink B, Bakker RA, de Esch IJ, Leurs R: Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives. J Med Chem. 2006 Jul 27;49(15):4512-6. [Article]
  4. Adachi N, Liu K, Motoki A, Nishibori M, Arai T: Suppression of ischemia/reperfusion liver injury by histamine H4 receptor stimulation in rats. Eur J Pharmacol. 2006 Aug 21;544(1-3):181-7. Epub 2006 Jun 29. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antagonist
General Function
Epinephrine binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine...
Gene Name
ADRA2B
Uniprot ID
P18089
Uniprot Name
Alpha-2B adrenergic receptor
Molecular Weight
49565.8 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Partial agonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
  2. Foster DJ, Bryant ZK, Conn PJ: Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021 May 7;405:113201. doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Partial agonist
General Function
G-protein coupled acetylcholine receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
  2. Foster DJ, Bryant ZK, Conn PJ: Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021 May 7;405:113201. doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
  2. Foster DJ, Bryant ZK, Conn PJ: Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021 May 7;405:113201. doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Partial agonist
General Function
Guanyl-nucleotide exchange factor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
  2. Foster DJ, Bryant ZK, Conn PJ: Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021 May 7;405:113201. doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM5
Uniprot ID
P08912
Uniprot Name
Muscarinic acetylcholine receptor M5
Molecular Weight
60073.205 Da
References
  1. Nasrallah HA: Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry. 2008 Jan;13(1):27-35. Epub 2007 Sep 11. [Article]
  2. Foster DJ, Bryant ZK, Conn PJ: Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021 May 7;405:113201. doi: 10.1016/j.bbr.2021.113201. Epub 2021 Feb 26. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Unknown
General Function
Clathrin light chain binding
Specific Function
Interacts with clathrin light chain A and stimulates clathrin self-assembly and clathrin-mediated endocytosis.
Gene Name
CALY
Uniprot ID
Q9NYX4
Uniprot Name
Neuron-specific vesicular protein calcyon
Molecular Weight
23433.49 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
S-nitrosoglutathione binding
Specific Function
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name
GSTP1
Uniprot ID
P09211
Uniprot Name
Glutathione S-transferase P
Molecular Weight
23355.625 Da
References
  1. Boerma JS, Vermeulen NP, Commandeur JN: Application of CYP102A1M11H as a tool for the generation of protein adducts of reactive drug metabolites. Chem Res Toxicol. 2011 Aug 15;24(8):1263-74. doi: 10.1021/tx2001515. Epub 2011 Jun 16. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Positive modulator
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR1
Uniprot ID
Q9UBS5
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 1
Molecular Weight
108319.4 Da
References
  1. Nair PC, McKinnon RA, Miners JO, Bastiampillai T: Binding of clozapine to the GABA(B) receptor: clinical and structural insights. Mol Psychiatry. 2020 Sep;25(9):1910-1919. doi: 10.1038/s41380-020-0709-5. Epub 2020 Mar 13. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Positive modulator
General Function
G-protein coupled gaba receptor activity
Specific Function
Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coup...
Gene Name
GABBR2
Uniprot ID
O75899
Uniprot Name
Gamma-aminobutyric acid type B receptor subunit 2
Molecular Weight
105820.52 Da
References
  1. Nair PC, McKinnon RA, Miners JO, Bastiampillai T: Binding of clozapine to the GABA(B) receptor: clinical and structural insights. Mol Psychiatry. 2020 Sep;25(9):1910-1919. doi: 10.1038/s41380-020-0709-5. Epub 2020 Mar 13. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Gene Name
GABRA1
Uniprot ID
P14867
Uniprot Name
Gamma-aminobutyric acid receptor subunit alpha-1
Molecular Weight
51801.395 Da
References
  1. Korpi ER, Wong G, Luddens H: Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1995 Oct;352(4):365-73. doi: 10.1007/BF00172773. [Article]
  2. Squires RF, Saederup E: Clozapine and some other antipsychotic drugs may preferentially block the same subset of GABA(A) receptors. Neurochem Res. 1997 Feb;22(2):151-62. doi: 10.1023/a:1027359422433. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...
Gene Name
GABRB1
Uniprot ID
P18505
Uniprot Name
Gamma-aminobutyric acid receptor subunit beta-1
Molecular Weight
54234.085 Da
References
  1. Korpi ER, Wong G, Luddens H: Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1995 Oct;352(4):365-73. doi: 10.1007/BF00172773. [Article]
  2. Squires RF, Saederup E: Clozapine and some other antipsychotic drugs may preferentially block the same subset of GABA(A) receptors. Neurochem Res. 1997 Feb;22(2):151-62. doi: 10.1023/a:1027359422433. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
Gene Name
GABRG1
Uniprot ID
Q8N1C3
Uniprot Name
Gamma-aminobutyric acid receptor subunit gamma-1
Molecular Weight
53594.49 Da
References
  1. Korpi ER, Wong G, Luddens H: Subtype specificity of gamma-aminobutyric acid type A receptor antagonism by clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1995 Oct;352(4):365-73. doi: 10.1007/BF00172773. [Article]
  2. Squires RF, Saederup E: Clozapine and some other antipsychotic drugs may preferentially block the same subset of GABA(A) receptors. Neurochem Res. 1997 Feb;22(2):151-62. doi: 10.1023/a:1027359422433. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Brosen K: Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995;29 Suppl 1:20-5. [Article]
  2. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [Article]
  3. Fang J, Coutts RT, McKenna KF, Baker GB: Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):592-9. [Article]
  4. Carrillo JA, Benitez J: Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet. 2000 Aug;39(2):127-53. [Article]
  5. Flockhart Table of Drug Interactions [Link]
  6. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Chetty M, Murray M: CYP-mediated clozapine interactions: how predictable are they? Curr Drug Metab. 2007 May;8(4):307-13. [Article]
  2. Prior TI, Baker GB: Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci. 2003 Mar;28(2):99-112. [Article]
  3. Fischer V, Vogels B, Maurer G, Tynes RE: The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J Pharmacol Exp Ther. 1992 Mar;260(3):1355-60. [Article]
  4. Clozapine Therapy and CYP2D6, CYP1A2, and CYP3A4 Genotypes [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Enzyme action is based on in vitro study findings.
General Function
Steroid hydroxylase activity
Specific Function
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Jung F, Richardson TH, Raucy JL, Johnson EF: Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C19 as low K(M) diazepam N-demethylases. Drug Metab Dispos. 1997 Feb;25(2):133-9. [Article]
  2. Chetty M, Murray M: CYP-mediated clozapine interactions: how predictable are they? Curr Drug Metab. 2007 May;8(4):307-13. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Prior TI, Chue PS, Tibbo P, Baker GB: Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol. 1999 Jun;9(4):301-9. [Article]
  2. Fang J, Coutts RT, McKenna KF, Baker GB: Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):592-9. [Article]
  3. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA: In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol. 1996 Mar;41(3):181-6. [Article]
  4. Chetty M, Murray M: CYP-mediated clozapine interactions: how predictable are they? Curr Drug Metab. 2007 May;8(4):307-13. [Article]
  5. Clozapine Therapy and CYP2D6, CYP1A2, and CYP3A4 Genotypes [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA: In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol. 1996 Mar;41(3):181-6. [Article]
  2. Fang J, Coutts RT, McKenna KF, Baker GB: Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):592-9. [Article]
  3. Prior TI, Chue PS, Tibbo P, Baker GB: Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol. 1999 Jun;9(4):301-9. [Article]
  4. Piatkov I, Caetano D, Assur Y, Lau SL, Coelho M, Jones T, Nguyen T, Boyages S, McLean M: CYP2C19*17 protects against metabolic complications of clozapine treatment. World J Biol Psychiatry. 2017 Oct;18(7):521-527. doi: 10.1080/15622975.2017.1347712. Epub 2017 Jul 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
The information supporting this enzyme action in the literature is limited to one study.
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Dragovic S, Gunness P, Ingelman-Sundberg M, Vermeulen NP, Commandeur JN: Characterization of human cytochrome P450s involved in the bioactivation of clozapine. Drug Metab Dispos. 2013 Mar;41(3):651-8. doi: 10.1124/dmd.112.050484. Epub 2013 Jan 7. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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 un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Fang J, Coutts RT, McKenna KF, Baker GB: Elucidation of individual cytochrome P450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):592-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Trimethylamine monooxygenase activity
Specific Function
Involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. It N-oxygenates primary aliphatic alkylamines as well as secondary and tertiary amines. Plays an impor...
Gene Name
FMO3
Uniprot ID
P31513
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 3
Molecular Weight
60032.975 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
General Function
Vitamin d 24-hydroxylase activity
Specific Function
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 un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Prior TI, Chue PS, Tibbo P, Baker GB: Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol. 1999 Jun;9(4):301-9. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Man WH, Wilting I, Heerdink ER, Hugenholtz GWK, Bognar T, Ten Berg MJ, van Solinge WW, Egberts TACG, van Maarseveen EM: Unbound Fraction of Clozapine Significantly Decreases with Elevated Plasma Concentrations of the Inflammatory Acute-Phase Protein Alpha-1-Acid Glycoprotein. Clin Pharmacokinet. 2019 Aug;58(8):1069-1075. doi: 10.1007/s40262-019-00744-6. [Article]
  2. Banis GE, Winkler T, Barton P, Chocron SE, Kim E, Kelly DL, Payne GF, Ben-Yoav H, Ghodssi R: The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study. Pharmaceuticals (Basel). 2017 Aug 1;10(3):69. doi: 10.3390/ph10030069. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Banis GE, Winkler T, Barton P, Chocron SE, Kim E, Kelly DL, Payne GF, Ben-Yoav H, Ghodssi R: The Binding Effect of Proteins on Medications and Its Impact on Electrochemical Sensing: Antipsychotic Clozapine as a Case Study. Pharmaceuticals (Basel). 2017 Aug 1;10(3):69. doi: 10.3390/ph10030069. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Boulton DW, DeVane CL, Liston HL, Markowitz JS: In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 2002 May 31;71(2):163-9. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Secondary active organic cation transmembrane transporter activity
Specific Function
Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnico...
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. Haenisch B, Drescher E, Thiemer L, Xin H, Giros B, Gautron S, Bonisch H: Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):1017-23. doi: 10.1007/s00210-012-0781-8. Epub 2012 Jul 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Quaternary ammonium group transmembrane transporter activity
Specific Function
Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. Haenisch B, Drescher E, Thiemer L, Xin H, Giros B, Gautron S, Bonisch H: Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):1017-23. doi: 10.1007/s00210-012-0781-8. Epub 2012 Jul 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Toxin transporter activity
Specific Function
Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.
Gene Name
SLC22A3
Uniprot ID
O75751
Uniprot Name
Solute carrier family 22 member 3
Molecular Weight
61279.485 Da
References
  1. Haenisch B, Drescher E, Thiemer L, Xin H, Giros B, Gautron S, Bonisch H: Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol. 2012 Oct;385(10):1017-23. doi: 10.1007/s00210-012-0781-8. Epub 2012 Jul 18. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 30, 2023 18:30