Identification

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Name
Doxepin
Accession Number
DB01142  (APRD00398)
Type
Small Molecule
Groups
Approved, Investigational
Description

Doxepin is a psychotropic agent with tricyclic antidepressant and anxiolytic properties.[9] It is a tertiary amine that can be presented as an (E) and (Z) stereoisomers from which the (Z) form corresponds to cidoxepin. The common products for doxepin included a racemic mixture 5:1 (E):(Z).[8]

In a strict sense, doxepin is not a tricyclic antidepressant but it is commonly associated with them as it shares a lot of properties with some of the members of this family such as amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, protriptyline and trimipramine.[13]

Doxepin was developed by Pfizer and FDA approved initially in 1969 as an antidepressive.[11] However, in 2010 it was approved for the treatment of insomnia. This later indication was presented by Pernix Therapeutics.[12]

Structure
Thumb
Synonyms
  • Doxepin
  • Doxepina
  • Doxepinum
External IDs
MF 10
Product Ingredients
IngredientUNIICASInChI Key
Doxepin hydrochloride3U9A0FE9N51229-29-4MHNSPTUQQIYJOT-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DoxepinCapsule100 mgOralAa Pharma Inc1993-12-31Not applicableCanada
DoxepinCapsule150 mgOralAa Pharma Inc1993-12-31Not applicableCanada
DoxepinCapsule25 mgOralAa Pharma Inc1993-12-31Not applicableCanada
DoxepinCapsule50 mgOralAa Pharma Inc1993-12-31Not applicableCanada
DoxepinCapsule75 mgOralAa Pharma Inc1993-12-31Not applicableCanada
DoxepinCapsule10 mgOralAa Pharma Inc1993-12-31Not applicableCanada
Doxepin HydrochlorideCapsule10 mg/1OralWatson Pharmaceuticals2007-10-25Not applicableUs
Doxepin HydrochlorideCapsule25 mg/1OralWatson Pharmaceuticals2007-10-25Not applicableUs
Doxepin HydrochlorideCapsule50 mg/1OralWatson Pharmaceuticals2007-10-25Not applicableUs
Doxepin HydrochlorideCapsule75 mg/1OralWatson Pharmaceuticals2007-10-25Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Alti-doxepin - Cap 10mgCapsule10 mgOralAltimed Pharma Inc.1995-12-312005-05-27Canada
Alti-doxepin-cap 25mgCapsule25 mgOralAltimed Pharma Inc.1995-12-312005-05-27Canada
Alti-doxepin-cap 50mgCapsule50 mgOralAltimed Pharma Inc.1995-12-312005-05-27Canada
Alti-doxepin-cap 75mgCapsule75 mgOralAltimed Pharma Inc.1995-12-312005-05-27Canada
Doxepin HydrochlorideCapsule75 mg/1OralTYA Pharmaceuticals1986-05-13Not applicableUs64725 537520180907 15195 14ydmah
Doxepin HydrochlorideCapsule10 mg/1OralMesource Pharmaceuticals1986-05-13Not applicableUs
Doxepin HydrochlorideCapsule50 mg/1OralH.J. Harkins Company2011-05-04Not applicableUs
Doxepin HydrochlorideCapsule75 mg/1OralRemedy Repack2006-11-142018-10-16Us
Doxepin HydrochlorideCapsule10 mg/1OralMylan Pharmaceuticals Inc.1986-05-13Not applicableUs0378 104920180913 8702 ti136x
Doxepin HydrochlorideCapsule25 mg/1OralMylan Pharmaceuticals Inc.1986-05-13Not applicableUs
International/Other Brands
Adapin (PennwaIt) / Aponal (Pfizer) / Curatin / Doxepine (Shou Chan) / Quitaxon (Lexphar)
Categories
UNII
5ASJ6HUZ7D
CAS number
1668-19-5
Weight
Average: 279.3761
Monoisotopic: 279.162314299
Chemical Formula
C19H21NO
InChI Key
ODQWQRRAPPTVAG-UHFFFAOYSA-N
InChI
InChI=1S/C19H21NO/c1-20(2)13-7-11-17-16-9-4-3-8-15(16)14-21-19-12-6-5-10-18(17)19/h3-6,8-12H,7,13-14H2,1-2H3
IUPAC Name
dimethyl(3-{9-oxatricyclo[9.4.0.0^{3,8}]pentadeca-1(15),3,5,7,11,13-hexaen-2-ylidene}propyl)amine
SMILES
[H]C(CCN(C)C)=C1C2=CC=CC=C2COC2=CC=CC=C12

Pharmacology

Indication

Oral doxepin is approved for the following indications:

  • Treatment of depression and/or anxiety.[1]
  • Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders.[7]
  • Treatment of psychotic depressive disorders with associated anxiety.[7]
  • Treatment of involutional depression.[7]
  • Treatment of manic-depressive disorder.[7]
  • Treatment of insomnia characterized by difficulties with sleep maintenance.[1]

Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus.[7]

Off-label, doxepin is used topically for the management of neuropathic pain.[2]

Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment.[14]

Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder.[15]

Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic.[16]

Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner.[17]

Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors.[18]

Associated Conditions
Pharmacodynamics

Similar to other tricyclic antidepressants, doxepin was showed, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression.[20]

Doxepin is known to present antidepressive, sedative and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its effect. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed.[1]

The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy.[6] However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration.[7]

Mechanism of action

Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker.[1] This effect on histamine receptors indicates effectiveness in skin conditions.[7]

Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites.[6] It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors.[7]

It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area.[7]

TargetActionsOrganism
AHistamine H1 receptor
antagonist
Humans
AHistamine H2 receptor
antagonist
Humans
ASodium-dependent noradrenaline transporter
inhibitor
Humans
ASodium-dependent serotonin transporter
inhibitor
Humans
U5-hydroxytryptamine receptor 2A
antagonist
Humans
U5-hydroxytryptamine receptor 2B
antagonist
Humans
U5-hydroxytryptamine receptor 2C
antagonist
Humans
UMuscarinic acetylcholine receptor M1
antagonist
Humans
UMuscarinic acetylcholine receptor M2
antagonist
Humans
UMuscarinic acetylcholine receptor M3
antagonist
Humans
UMuscarinic acetylcholine receptor M4
antagonist
Humans
UMuscarinic acetylcholine receptor M5
antagonist
Humans
UAlpha-1A adrenergic receptor
antagonist
Humans
UAlpha-1B adrenergic receptor
antagonist
Humans
UAlpha-1D adrenergic receptor
antagonist
Humans
U5-hydroxytryptamine receptor 1A
antagonist
Humans
U5-hydroxytryptamine receptor 6
binder
Humans
UHistamine H4 receptor
binder
Humans
UPotassium voltage-gated channel subfamily H member 2
inhibitor
Humans
Absorption

Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%.[6] The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal.[19]

Volume of distribution

The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg.[6]

Protein binding

Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin.[3]

Metabolism

Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites.[2] The first-pass metabolism accounts for 55-87% of the administered dose.[5] After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates.[19]

The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9.[19]

Route of elimination

The elimination profile of doxepin is presented as biphasic.[3] It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin.[10]

Half life

The mean elimination half-life is reported to be of 15 hours.[6]

Clearance

The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg.[3]

Toxicity

Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively.[MSDS] In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed.[7]

On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential.[Label]

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Doxepin H1-Antihistamine ActionDrug action
Doxepin Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2D6CYP2D6*3Not Available2549delAEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableA alleleEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2C19CYP2C19*2Not Available681G>AEffect Directly StudiedThe presence of this polymorphism in CYP2C19 is associated with poor metabolism of doxepin.Details
Cytochrome P450 2C19CYP2C19*3Not Available636G>AEffect Directly StudiedThe presence of this polymorphism in CYP2C19 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.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. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor drug metabolizer. For individual with two non-functional alleles, dose reduction recommended.Details
Cytochrome P450 2D6CYP2D6*3Not AvailableG alleleEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details
Cytochrome P450 2D6CYP2D6*4Not Available3877G>AEffect Directly StudiedThe presence of this polymorphism in CYP2D6 is associated with reduced or poor metabolism of doxepin.Details

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Doxepin can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Doxepin can be decreased when combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when Doxepin is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
1-benzylimidazoleThe risk or severity of hypertension can be increased when Doxepin is combined with 1-benzylimidazole.
1,10-PhenanthrolineThe therapeutic efficacy of Doxepin can be decreased when used in combination with 1,10-Phenanthroline.
2,4-thiazolidinedioneDoxepin may decrease the hypoglycemic activities of 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamineThe therapeutic efficacy of Doxepin can be decreased when used in combination with 2,5-Dimethoxy-4-ethylamphetamine.
2,5-Dimethoxy-4-ethylthioamphetamineThe therapeutic efficacy of Doxepin can be decreased when used in combination with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,5-diiodothyropropionic acidThe metabolism of Doxepin can be decreased when combined with 3,5-diiodothyropropionic acid.
4-Bromo-2,5-dimethoxyamphetamineThe therapeutic efficacy of Doxepin can be decreased when used in combination with 4-Bromo-2,5-dimethoxyamphetamine.
Food Interactions
  • Avoid alcohol.
  • Avoid excessive quantities of coffee or tea (caffeine).
  • Avoid St.John's Wort.
  • Take with food to reduce irritation.

References

Synthesis Reference
US20090074862
General References
  1. Rojas-Fernandez CH, Chen Y: Use of ultra-low-dose (PubMed:25364337]
  2. Authors unspecified: Doxepin . [PubMed:30000240]
  3. Virtanen R, Scheinin M, Iisalo E: Single dose pharmacokinetics of doxepin in healthy volunteers. Acta Pharmacol Toxicol (Copenh). 1980 Nov;47(5):371-6. [PubMed:7293791]
  4. Singh H, Becker PM: Novel therapeutic usage of low-dose doxepin hydrochloride. Expert Opin Investig Drugs. 2007 Aug;16(8):1295-305. [PubMed:17685877]
  5. Negrusz A, Moore CM, Perry JL: Detection of doxepin and its major metabolite desmethyldoxepin in hair following drug therapy. J Anal Toxicol. 1998 Oct;22(6):531-6. [PubMed:9788530]
  6. Pagliaro L. and Pagliaro A. (1999). Psychologists' psychotropic drug reference. Taylor and Francis.
  7. Stephen M. Stahl (2006). Essential Psychopharmacology: The Prescriber's Guide: Revised and Updated Edition. Cambridge University Press. [ISBN:9780521683500]
  8. Elks J. and Ganellin C.R. (1990). The dictionary of drugs. Springer Science.
  9. Bishop M. (2015). Clinical chemistry: techniques, principles and correlations (6th ed.). Content Technologies Inc. [ISBN:978-146-7263-085]
  10. FDA Label: SilenorTM (doxepin) tablets for oral administration [Link]
  11. FDA approvals [Link]
  12. FDA approvals [Link]
  13. Encyclopedia [Link]
  14. American Psychiatric Association [Link]
  15. Canadian Mental Health Association [Link]
  16. HealthLink BC [Link]
  17. Cleveland Clinic [Link]
  18. Merck Manuals [Link]
  19. Dehli Psychiatry Journal paper [Link]
  20. Novo-doxepin product monograph [Link]
External Links
Human Metabolome Database
HMDB0015273
KEGG Drug
D07875
KEGG Compound
C06971
PubChem Compound
667468
PubChem Substance
46505232
ChemSpider
3046
BindingDB
50079527
ChEBI
4710
ChEMBL
CHEMBL1628227
Therapeutic Targets Database
DAP000177
PharmGKB
PA449409
IUPHAR
1225
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Doxepin
ATC Codes
N06AA12 — DoxepinD04AX01 — Doxepin
AHFS Codes
  • 84:08.00 — Antipruritics and Local Anesthetics
  • 28:16.04.28 — Tricyclics and Other Norepinephrine-reuptake Inhibitors
PDB Entries
3rze
FDA label
Download (128 KB)
MSDS
Download (585 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentParkinson's Disease (PD) / Sleeplessness1
2CompletedTreatmentIrritable Bowel Syndrome (IBS)1
2CompletedTreatmentSleep Initiation and Maintenance Disorders1
2RecruitingPreventionCancer, Breast1
3Active Not RecruitingSupportive CareHead and Neck Carcinoma / Mucositis / Oral Complications of Radiation Therapy / Pain NOS1
3CompletedTreatmentAcute Oral Mucositis Pain1
3TerminatedTreatmentAnxiety Disorders / Dementias / Depression / Psychosomatic Disorders / Schizophrenic Disorders1
4CompletedDiagnosticHealthy Volunteers1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Sleeplessness1
Not AvailableCompletedSupportive CareAdvanced thymic carcinoma / Hypopharyngeal Carcinoma / Laryngeal Carcinoma / Lung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancer Small Cell Lung Cancer (SCLC) / Malignant Lymphomas / Malignant Pericardial Effusion / Malignant Pleural Effusions / Mesothelioma / Mesothelioma, Malignant / Metastatic Malignant Neoplasm in the Lung / Metastatic Malignant Neoplasm in the Pleura / Metastatic Malignant Neoplasm in the Spinal Cord / Non-Small Cell Lung Carcinoma (NSCLC) / Oesophageal Carcinoma / Sarcomas / Small Cell Lung Carcinoma / Soft Tissue Sarcoma (STS) / Thymic Carcinoma / Thymoma and Thymic Carcinoma / Thyroid Gland Carcinoma1
Not AvailableEnrolling by InvitationNot AvailableBipolar Disorder (BD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Advanced Pharmaceutical Services Inc.
  • Amerisource Health Services Corp.
  • A-S Medication Solutions LLC
  • Bioglan Pharmaceuticals Co.
  • Coupler Enterprises Inc.
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • DPT Laboratories Ltd.
  • Healthpoint Ltd.
  • Heartland Repack Services LLC
  • Innoviant Pharmacy Inc.
  • Lederle Arzneimittel Cyanamid GmbH
  • Liberty Pharmaceuticals
  • Major Pharmaceuticals
  • Medisca Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • Par Pharmaceuticals
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pfizer Inc.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Pharmaderm
  • Pharmedix
  • Physicians Total Care Inc.
  • Preferred Pharmaceuticals Inc.
  • Prepackage Specialists
  • Prepak Systems Inc.
  • Prescript Pharmaceuticals
  • Qualitest
  • Rebel Distributors Corp.
  • Remedy Repack
  • Silarx Pharmaceuticals
  • Southwood Pharmaceuticals
  • Stat Rx Usa
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • United Research Laboratories Inc.
  • Watson Pharmaceuticals
  • Wockhardt Ltd.
Dosage forms
FormRouteStrength
CapsuleOral10 mg/1
CapsuleOral100 mg/1
CapsuleOral150 mg/1
CapsuleOral25 mg/1
CapsuleOral50 mg/1
CapsuleOral75 mg/1
SolutionOral10 mg/1mL
CapsuleOral150 mg
TabletOral3 mg/1
TabletOral3.00 mg
TabletOral6 mg/1
TabletOral6.00 mg
Solution, concentrateOral10 mg/1mL
CapsuleOral100 mg
CapsuleOral10 mg
CapsuleOral25 mg
CapsuleOral50 mg
CapsuleOral75 mg
CreamTopical50 mg/1g
CreamTopical5 %
Prices
Unit descriptionCostUnit
Zonalon 5% Cream 45 gm Tube190.13USD tube
Zonalon 5% Cream 30 gm Tube144.29USD tube
Doxepin hcl powder8.88USD g
Doxepin 150 mg capsule3.33USD capsule
Prudoxin 5% cream3.05USD g
Sinequan 100 mg Capsule1.22USD capsule
Novo-Doxepin 150 mg Capsule1.18USD capsule
Sinequan 75 mg Capsule0.93USD capsule
Zonalon 5% cream0.89USD g
Doxepin HCl 150 mg capsule0.87USD capsule
Apo-Doxepin 100 mg Capsule0.68USD capsule
Novo-Doxepin 100 mg Capsule0.68USD capsule
Sinequan 50 mg Capsule0.64USD capsule
Doxepin 50 mg capsule0.57USD capsule
Doxepin HCl 100 mg capsule0.56USD capsule
Novo-Doxepin 75 mg Capsule0.52USD capsule
Apo-Doxepin 75 mg Capsule0.52USD capsule
Doxepin HCl 75 mg capsule0.43USD capsule
Apo-Doxepin 50 mg Capsule0.36USD capsule
Novo-Doxepin 50 mg Capsule0.36USD capsule
Sinequan 25 mg Capsule0.35USD capsule
Doxepin 10 mg capsule0.32USD capsule
Sinequan 10 mg Capsule0.28USD capsule
Doxepin HCl 50 mg capsule0.25USD capsule
Doxepin HCl 25 mg capsule0.23USD capsule
Doxepin 75 mg capsule0.21USD capsule
Doxepin HCl 10 mg capsule0.21USD capsule
Apo-Doxepin 10 mg Capsule0.2USD capsule
Apo-Doxepin 25 mg Capsule0.19USD capsule
Novo-Doxepin 25 mg Capsule0.19USD capsule
Doxepin 25 mg capsule0.18USD capsule
Doxepin 100 mg capsule0.14USD capsule
Doxepin HCl 10 mg/ml Concentrate0.13USD ml
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Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6211229No2001-04-032020-02-17Us
US9107898No2015-08-182028-05-01Us
US8513299No2013-08-202030-04-14Us
US7915307No2011-03-292027-08-24Us
US9532971No2017-01-032029-06-01Us
US9486437No2016-11-082027-05-18Us
US9572814No2017-02-212027-07-20Us
US9861607No2018-01-092027-05-18Us
US9907780No2018-03-062028-04-11Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)185-191 ºC'MSDS'
boiling point (°C)154-157 ºC at 0.03 mmHgBudavari S. 1996. The Merck Index.
water solubility31.6 mg/L (at 25 °C)Yalkowsky S. et al. 1992. Aquasol Database of Aqueous Solubility.
logP4.29Maslanka A. et al. 2011. J AOAC Int.
pKa8.96Embil K. and Torosian G. 1982. J Pharm Sci.
Predicted Properties
PropertyValueSource
Water Solubility0.0319 mg/mLALOGPS
logP4.08ALOGPS
logP3.84ChemAxon
logS-3.9ALOGPS
pKa (Strongest Basic)9.76ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity98.24 m3·mol-1ChemAxon
Polarizability32.47 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9931
Blood Brain Barrier+0.9381
Caco-2 permeable+0.8108
P-glycoprotein substrateSubstrate0.8147
P-glycoprotein inhibitor IInhibitor0.8147
P-glycoprotein inhibitor IIInhibitor0.8214
Renal organic cation transporterInhibitor0.7883
CYP450 2C9 substrateNon-substrate0.7846
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateSubstrate0.7475
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.917
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6362
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.8322
BiodegradationNot ready biodegradable0.8461
Rat acute toxicity3.2478 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.5346
hERG inhibition (predictor II)Inhibitor0.6959
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-QFT , positiveLC-MS/MSsplash10-001i-0090000000-c6d70f4744a166243d9c
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-1290000000-843ca75cae9c06d5a947
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0a4i-3940000000-053eb0b8a655ffc47644
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0a4i-3920000000-1decbf30162661f4429b
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0a4i-4920000000-7a9368d04bc38800e87e
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-05ox-4920000000-e6f843926675f1d98789
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-016r-4910000000-1ea8272c7a2859f70a82
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-014i-4910000000-567d6be4466beea7456e
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-014r-4900000000-ce29d6e3479d635e3995

Taxonomy

Description
This compound belongs to the class of organic compounds known as dibenzoxepines. These are compounds containing a dibenzoxepine moiety, which consists of two benzene connected by an oxazepine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzoxepines
Sub Class
Dibenzoxepines
Direct Parent
Dibenzoxepines
Alternative Parents
Alkyl aryl ethers / Benzenoids / Trialkylamines / Oxacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Dibenzoxepine / Alkyl aryl ether / Benzenoid / Tertiary aliphatic amine / Tertiary amine / Oxacycle / Ether / Organic nitrogen compound / Organic oxygen compound / Organopnictogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, dibenzooxepine (CHEBI:4710)

Targets

Details
1. Histamine H1 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Curator comments
Ki < 1 nM
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. Tashiro M, Sakurada Y, Iwabuchi K, Mochizuki H, Kato M, Aoki M, Funaki Y, Itoh M, Iwata R, Wong DF, Yanai K: Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol. 2004 Aug;44(8):890-900. [PubMed:15286093]
  2. Tran VT, Lebovitz R, Toll L, Snyder SH: [3H]doxepin interactions with histamine H1-receptors and other sites in guinea pig and rat brain homogenates. Eur J Pharmacol. 1981 Apr 9;70(4):501-9. [PubMed:7238574]
  3. Kano M, Fukudo S, Tashiro A, Utsumi A, Tamura D, Itoh M, Iwata R, Tashiro M, Mochizuki H, Funaki Y, Kato M, Hongo M, Yanai K: Decreased histamine H1 receptor binding in the brain of depressed patients. Eur J Neurosci. 2004 Aug;20(3):803-10. [PubMed:15255990]
  4. Claro E, Arbones L, Garcia A, Picatoste F: Phosphoinositide hydrolysis mediated by histamine H1-receptors in rat brain cortex. Eur J Pharmacol. 1986 Apr 16;123(2):187-96. [PubMed:3011460]
  5. Richelson E, Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther. 1984 Jul;230(1):94-102. [PubMed:6086881]
  6. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  7. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  8. Singh H, Becker PM: Novel therapeutic usage of low-dose doxepin hydrochloride. Expert Opin Investig Drugs. 2007 Aug;16(8):1295-305. [PubMed:17685877]
  9. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
  10. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Details
2. Histamine H2 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and diff...
Gene Name
HRH2
Uniprot ID
P25021
Uniprot Name
Histamine H2 receptor
Molecular Weight
40097.65 Da
References
  1. Beil W, Hannemann H, Sewing KF: Interaction of antidepressants and neuroleptics with histamine stimulated parietal cell adenylate cyclase and H+ secretion. Pharmacology. 1988;36(3):198-203. [PubMed:2897127]
  2. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Pagliaro L. and Pagliaro A. (1999). Psychologists' psychotropic drug reference. Taylor and Francis.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Pagliaro L. and Pagliaro A. (1999). Psychologists' psychotropic drug reference. Taylor and Francis.
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Maj J, Gancarczyk L, Gorszczyk L, Rawlow A: Doxepin as a blocker of central serotonin receptors. Pharmakopsychiatr Neuropsychopharmakol. 1977 Dec;10(6):318-24. [PubMed:309138]
  3. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
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 ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation...
Gene Name
HTR2B
Uniprot ID
P41595
Uniprot Name
5-hydroxytryptamine receptor 2B
Molecular Weight
54297.41 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Maj J, Gancarczyk L, Gorszczyk L, Rawlow A: Doxepin as a blocker of central serotonin receptors. Pharmakopsychiatr Neuropsychopharmakol. 1977 Dec;10(6):318-24. [PubMed:309138]
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Maj J, Gancarczyk L, Gorszczyk L, Rawlow A: Doxepin as a blocker of central serotonin receptors. Pharmakopsychiatr Neuropsychopharmakol. 1977 Dec;10(6):318-24. [PubMed:309138]
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
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Ehlert FJ, Delen FM, Yun SH, Liem HA: The interaction of amitriptyline, doxepin, imipramine and their N-methyl quaternary ammonium derivatives with subtypes of muscarinic receptors in brain and heart. J Pharmacol Exp Ther. 1990 Apr;253(1):13-9. [PubMed:2329499]
  4. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Ehlert FJ, Delen FM, Yun SH, Liem HA: The interaction of amitriptyline, doxepin, imipramine and their N-methyl quaternary ammonium derivatives with subtypes of muscarinic receptors in brain and heart. J Pharmacol Exp Ther. 1990 Apr;253(1):13-9. [PubMed:2329499]
  3. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Ehlert FJ, Delen FM, Yun SH, Liem HA: The interaction of amitriptyline, doxepin, imipramine and their N-methyl quaternary ammonium derivatives with subtypes of muscarinic receptors in brain and heart. J Pharmacol Exp Ther. 1990 Apr;253(1):13-9. [PubMed:2329499]
  3. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Ehlert FJ, Delen FM, Yun SH, Liem HA: The interaction of amitriptyline, doxepin, imipramine and their N-methyl quaternary ammonium derivatives with subtypes of muscarinic receptors in brain and heart. J Pharmacol Exp Ther. 1990 Apr;253(1):13-9. [PubMed:2329499]
  3. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Ehlert FJ, Delen FM, Yun SH, Liem HA: The interaction of amitriptyline, doxepin, imipramine and their N-methyl quaternary ammonium derivatives with subtypes of muscarinic receptors in brain and heart. J Pharmacol Exp Ther. 1990 Apr;253(1):13-9. [PubMed:2329499]
  3. Figueiredo A, Ribeiro CA, Goncalo M, Almeida L, Poiares-Baptista A, Teixeira F: Mechanism of action of doxepin in the treatment of chronic urticaria. Fundam Clin Pharmacol. 1990;4(2):147-58. [PubMed:2141000]
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Richelson E, Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther. 1984 Jul;230(1):94-102. [PubMed:6086881]
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
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Richelson E, Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther. 1984 Jul;230(1):94-102. [PubMed:6086881]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
References
  1. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Stahl SM: Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines. CNS Spectr. 2008 Dec;13(12):1027-38. [PubMed:19179941]
  3. Richelson E, Nelson A: Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther. 1984 Jul;230(1):94-102. [PubMed:6086881]
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. Cusack B, Nelson A, Richelson E: Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. [PubMed:7855217]
  2. Maj J, Gancarczyk L, Gorszczyk L, Rawlow A: Doxepin as a blocker of central serotonin receptors. Pharmakopsychiatr Neuropsychopharmakol. 1977 Dec;10(6):318-24. [PubMed:309138]
  3. Stephen M. Stahl (2006). Essential Psychopharmacology: The Prescriber's Guide: Revised and Updated Edition. Cambridge University Press. [ISBN:9780521683500]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
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. PDSP Ki Database [Link]
Details
18. Histamine H4 receptor
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
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. PDSP Ki Database [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. Duncan RS, McPate MJ, Ridley JM, Gao Z, James AF, Leishman DJ, Leaney JL, Witchel HJ, Hancox JC: Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin. Biochem Pharmacol. 2007 Aug 1;74(3):425-37. Epub 2007 May 3. [PubMed:17560554]

Enzymes

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. Szewczuk-Boguslawska M, Kiejna A, Beszlej JA, Orzechowska-Juzwenko K, Milejski P: Doxepin inhibits CYP2D6 activity in vivo. Pol J Pharmacol. 2004 Jul-Aug;56(4):491-4. [PubMed:15520506]
  2. Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A, Muller M, Hiemke C, Freymann N, Zobel A, Maier W, Rao ML: Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol. 2004 Jul;60(5):329-36. Epub 2004 May 28. [PubMed:15168101]
  3. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J: Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002 Oct;12(7):571-80. [PubMed:12360109]
  4. Haritos VS, Ghabrial H, Ahokas JT, Ching MS: Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin. Pharmacogenetics. 2000 Oct;10(7):591-603. [PubMed:11037801]
  5. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  6. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J: Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002 Oct;12(7):571-80. [PubMed:12360109]
  2. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C: The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res. 2002 Jul;19(7):1034-7. [PubMed:12180536]
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J: Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 2002 Oct;12(7):571-80. [PubMed:12360109]
  2. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C: The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res. 2002 Jul;19(7):1034-7. [PubMed:12180536]
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
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. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C: The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res. 2002 Jul;19(7):1034-7. [PubMed:12180536]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  3. Doxepin FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C: The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm Res. 2002 Jul;19(7):1034-7. [PubMed:12180536]

Carriers

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. Virtanen R, Iisalo E, Irjala K: Protein binding of doxepin and desmethyldoxepin. Acta Pharmacol Toxicol (Copenh). 1982 Aug;51(2):159-64. [PubMed:7113722]
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. Virtanen R, Iisalo E, Irjala K: Protein binding of doxepin and desmethyldoxepin. Acta Pharmacol Toxicol (Copenh). 1982 Aug;51(2):159-64. [PubMed:7113722]

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. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW: Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37. [PubMed:12438524]
  2. FDA reports [Link]

Drug created on June 13, 2005 07:24 / Updated on April 19, 2019 16:00