PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
clomipramine

2D structure

Overview

Generic Names: 3-Chloroimipramine; Chlorimipramine; Clomipramina [INN-Spanish]; Clomipramine HCL; Clomipraminum [INN-Latin]; Monochlorimipramine
Trade Names: Anafranil; Hydiphen
PharmGKB Accession Id: PA449048

Description

A tricyclic antidepressant similar to imipramine that selectively inhibits the uptake of serotonin in the brain. It is readily absorbed from the gastrointestinal tract and demethylated in the liver to form its primary active metabolite, desmethylclomipramine. PubChem (source: Drug Bank)

Indication

For the treatment of depression, obsessive compulsive disorder (OCD), panic attacks with or without agoraphobia, narcolepsy, chronic pain, and enuresis. (source: Drug Bank)

ATC Therapeutic Category

  • N06AA:Non-selective monoamine reuptake inhibitors

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Clomipramine is a strong, but not completely selective Serotonic-Reuptake-Inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of Noradrenaline-Reuptake. Alpha-1-Receptor blockage and beta-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. (source: Drug Bank)

Pharmacology

Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: alpha-1 and beta-1 receptors are sensitized, alpha-2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. (source: Drug Bank)

Food Interactions

Avoid alcohol.
Grapefruit and grapefruit juice should be avoided throughout treatment, grapefruit can modify serum levels of clomipramine and its metabolite desmethyl-clomipramine.
Take with food to reduce irritation. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. The main active metabolite is desmethylclomipramine. (source: Drug Bank)

Protein Binding

97% (source: Drug Bank)

Absorption

Bioavailability is approximately 50% orally. (source: Drug Bank)

Toxicity

Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. (source: Drug Bank)

Isomeric SMILES Code:

CN(C)CCCN1c2ccccc2CCc3c1cc(cc3)Cl (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs11188072 at chr10:96509051 in CYP2C19
    This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.
    Variant Name:
    CYP2C19: -3402C>T
    Related Drugs:
    amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
    Evidence:
    PMID:16413245
    PMID:17625515
    PMID:18294333
  2. rs12248560 at chr10:96511647 in CYP2C19
    This promoter variant is part of CYP2C19*17 haplotype, which causes increased acitivity and increased transcription of CYP2C19. Patients carrying this allele may exhibit a lack of response to commonly prescribed dosages of certain proton pump inhibitors (PPIs) and antidepressants, due to ultrarapid clearance of these drugs. CYP2C19*17 carriers are more likely to benifit from tamoxifen treatment.
    Variant Name:
    CYP2C19: -806C>T
    Related Drugs:
    amitriptyline, citalopram, clomipramine, escitalopram, omeprazole, proguanil, tamoxifen
    Evidence:
    PMID:16413245
    PMID:18024866
  3. rs3892097 at chr22:40854891 in CYP2D6
    The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians. A number of studies show that poor metabolizer (PMs:*4/*4) reqiure a lower dose of drugs which get metabolized by CYP2D6.
    Variant Name:
    CYP2D6*4
    Related Drugs:
    clomipramine, codeine, desipramine, imipramine, nortriptyline, venlafaxine
    Related Diseases:
    Drug Toxicity
    Evidence:
    PMID:16958828
    PMID:1782973
    PMID:18070221
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
  • CO
  • PD
  • PK
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
CYP2A6
  • CO
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2B6
  • CO
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  • CO
  • PD
  • PK
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  • CO
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  • CO
  • PD
  • PK
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  • CO
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available No genotype data Literature annotations available Has annotations
PTGS2
  •   
  • PD
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
SLC6A4
  • CO
  •   
  •   
  •   
  • GN
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
HTR2A Uncurated Annotation (source: Drug Bank)
GSTP1 Uncurated Annotation (source: Drug Bank)
SLC6A2 Uncurated Annotation (source: Drug Bank)
SLC6A4 Uncurated Annotation (source: Drug Bank)

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
tamoxifen
  •   
  •   
  •   
  •   
  •   
Publications

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
altretamine Uncurated Annotation Risk of severe hypotension (source: Drug Bank)
atazanavir Uncurated Annotation Atazanavir increases the effect and toxicity of tricyclics (source: Drug Bank)
cimetidine Uncurated Annotation Cimetidine increases the effect of tricyclic agent (source: Drug Bank)
cisapride Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
clonidine Uncurated Annotation The tricycli decreases the effect of clonidine (source: Drug Bank)
dobutamine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
donepezil Uncurated Annotation Possible antagonism of action (source: Drug Bank)
dopamine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
ephedra Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
ephedrine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
epinephrine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
fenoterol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
fluoxetine Uncurated Annotation Fluoxetine increases the effect and toxicity of tricyclics (source: Drug Bank)
fluvoxamine Uncurated Annotation Fluvoxamine increases the effect and toxicity of tricyclics (source: Drug Bank)
galantamine Uncurated Annotation Possible antagonism of action (source: Drug Bank)
grepafloxacin Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
guanethidine Uncurated Annotation The tricyclic decreases the effect of guanethidine (source: Drug Bank)
isocarboxazid Uncurated Annotation Possibility of severe adverse effects (source: Drug Bank)
isoproterenol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
mephentermine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
metaraminol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
methoxamine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
moclobemide Uncurated Annotation Possible severe adverse reaction with this combination (source: Drug Bank)
norepinephrine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
orciprenaline Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
phenelzine Uncurated Annotation Possibility of severe adverse effects (source: Drug Bank)
phenylephrine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
phenylpropanolamine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
pirbuterol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
procaterol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
pseudoephedrine Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
quinidine Uncurated Annotation Quinidine increases the effect of tricyclic agent (source: Drug Bank)
quinidine Uncurated Annotation Quinidine increases the effect of tricyclic agent (source: Drug Bank)
rasagiline Uncurated Annotation Possibility of severe adverse effects (source: Drug Bank)
rifabutin Uncurated Annotation The rifamycin decreases the effect of tricyclics (source: Drug Bank)
rifampin Uncurated Annotation The rifamycin decreases the effect of tricyclics (source: Drug Bank)
ritonavir Uncurated Annotation Ritonavir increases the effect and toxicity of tricyclics (source: Drug Bank)
rivastigmine Uncurated Annotation Possible antagonism of action (source: Drug Bank)
salbutamol Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
sibutramine Uncurated Annotation Increased risk of CNS adverse effects (source: Drug Bank)
sparfloxacin Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
terbutaline Uncurated Annotation The tricyclic increases the sympathomimetic effect (source: Drug Bank)
terfenadine Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
tranylcypromine Uncurated Annotation Possibility of severe adverse effects (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
Phenotype data available No genotype data Literature annotations available Not annotated
Depression
  • CO
  • PD
  • PK
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Depression, Postpartum
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Drug Toxicity
  •   
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Inflammation
  •   
  • PD
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Neoplasms
  • CO
  • PD
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Schizophrenia
  • CO
  • PD
  • PK
  •   
  •   
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01242
KEGG Compound ID:
C06918
PubChem Compound ID:
2801
PubChem Substance ID:
152550
IUPHAR Ligand ID:
2398

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

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