The compound is a potent and selective histamine receptor H1 antagonist. It also acts as an antagonist at histamine, serotonin, adrenergic, and muscarinic receptors with Ki values in the nanomolar range. It inhibits the reuptake of serotonin and norepinephrine.

Doxepin's protective effect is associated with increased PSD-95 and synaptophysin 1 expression via PI3K/AKT/mTOR signaling [6].
Doxepin hydrochloride is a tricyclic antidepressant that inhibits the reuptake of serotonin and norepinephrine. It is a potent H1 histamine receptor antagonist (Kd = 310 pM) and also binds to the H4 histamine receptor (pKi = 6.79). The compound has therapeutic effects in atopic dermatitis and chronic urticaria.

Aβ1-42-induced memory impairment is protected against by doxepin hydrochloride (doxepin 1 mg/kg and 5 mg/kg intraperitoneally, once a day for 21 days) [6].
Doxepin hydrochloride is used to treat depression, anxiety, and insomnia. It is also used to treat chronic pain, itching, and other medical conditions. The compound has potent antidepressant, anxiolytic, and sedative properties. It can improve cognitive processes and protect the central nervous system.

In vitro receptor binding assays for Doxepin hydrochloride typically use membrane preparations from cells expressing histamine H1, serotonin, adrenergic, or muscarinic receptors. Radiolabeled ligands specific for each receptor are displaced by increasing concentrations of the compound to determine binding affinity (Ki). Non-specific binding is determined in the presence of excess unlabeled ligand. Functional assays measure receptor-mediated signaling inhibition.

Western Blot analysis
Cell Types: SH-SY5Y human neuroblastoma cell line
Tested Concentrations: 10 ng/ml
Incubation Duration: 2 h
Experimental Results: Increased protein expression of PSD-95, synaptophysin 1 and p-AKT in SH-SY5Y cells levels, reducing the protein expression level of p-mTOR in SH-SY5Y cells.
Cell-based functional assays for Doxepin hydrochloride involve measuring its effects on neurotransmitter uptake or receptor signaling. Serotonin and norepinephrine uptake assays use cells expressing the respective transporters. Cells are incubated with radiolabeled neurotransmitters and the compound, and uptake is measured. Receptor signaling assays measure calcium mobilization or cAMP accumulation. The compound's antagonism of histamine H1 receptor signaling is assessed.

Animal/Disease Models: SD male rats [6].
Doses: 1, 5 mg/kg
Route of Administration: Doxepin (doxepin intraperitoneally (ip) (ip) injected one time/day for 21 days, intraperitoneal (ip) injection 1 mg/kg and 5 mg/kg)
Experimental Results: Increased hippocampus and temporal lobe PSD-95 and synaptophysin 1 protein expression levels. After treatment with 1 mg/kg doxepin, the p-AKT protein expression levels in the hippocampus and temporal lobes of rats were diminished.
In vivo animal studies for Doxepin hydrochloride typically involve administering the compound to rodent models of depression, anxiety, or insomnia. Behavioral tests (e.g., forced swim test, elevated plus maze, tail suspension test) are performed to assess antidepressant and anxiolytic effects. Sleep studies are conducted to evaluate sedative properties. The compound's effects on neurotransmitter levels in the brain are measured by microdialysis.

Absorption, Distribution and Excretion
Oral absorption of doxepin is moderate, with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8 to 45.8 ng/ml, reached 3.5 hours after the first dose. Concomitant administration with a high-fat meal may increase absorption.
The elimination curve of doxepin is biphasic. It is primarily excreted in the urine as a glucuronide conjugate.
Less than 3% of the dose of doxepin is excreted in the urine as unchanged drug or nordoxepin.
The reported mean apparent volume of distribution of doxepin is 20 L/kg.
The mean total apparent plasma clearance after a single oral dose of 50 mg doxepin in healthy individuals is 0.93 L/hr/kg.
/Doxepin/...has a specific affinity for uveal melanin...and...binds to ocular melanin both in vivo and in vitro. Assuming complete absorption, the estimated first-pass metabolism rate after oral administration of 75 mg doxepin hydrochloride in humans is 55-87% of the oral dose. The pharmacokinetics of doxepin have not been extensively studied, but the drug is well absorbed in the gastrointestinal tract. In animals, peak plasma concentrations are reached within 2 hours after oral administration. Limited data suggest that doxepin and its active N-demethylated metabolite are distributed into breast milk, reportedly at concentrations of approximately 30-140% and 10-115% of maternal serum concentrations, respectively. Furthermore, high concentrations of the active metabolite have been detected in the serum and urine of lactating infants whose mothers have taken 75-150 mg of doxepin daily. Metabolism/Metabolites: Doxepin is primarily metabolized to the biologically active metabolite N-demethyldoxepin and other inactive metabolites. First-pass metabolism accounts for 55-87% of the administered dose. Subsequently, secondary metabolism is primarily driven by the conversion of N-demethyldoxepin to its glucuronide conjugate. The main metabolic enzymes involved in the metabolism of doxepin are cytochrome P450 family members CYP2C19 and CYP2D6, with less involvement from CYP1A2 and CYP2C9. Oral administration of doxepin hydrochloride produces the metabolite desmethyldoxepin. Known human metabolites of doxepin include doxepin N-glucuronide. The reported mean elimination half-life is 15 hours. After oral administration of 75 mg doxepin hydrochloride, peak plasma concentrations reach 8.8–45.8 ng/mL within 4 hours. The disappearance of doxepin is biphasic and follows first-order kinetics. The mean half-life of doxepin is 16.8 hours. The mean apparent volume of distribution is 20.2 L/kg.
Pharmacokinetic properties of Doxepin hydrochloride are well-characterized from clinical use. The compound is orally bioavailable. It is highly protein-bound and widely distributed in tissues. Metabolism occurs primarily in the liver via CYP450 enzymes (CYP2D6 and CYP3A4). The active metabolite, nordoxepin, contributes to the therapeutic effect. Excretion occurs through renal pathways. The compound has a half-life of approximately 8-24 hours.

Interactions
Doxepin may enhance the inhibitory effect of alcohol. At a dose of 200-300 mg/day, doxepin may inhibit the hypotensive effect of guanethidine. Doxepin may enhance the effects of oral anticoagulants, amphetamines, other anticholinergic drugs, meprobamate, phenothiazines, and thioxanthidine sedatives. Theoretically, doxepin may antagonize the effects of propranolol and methyldopa. Barbiturates may antagonize the effects of doxepin. Doxepin may have its effects enhanced by thyroid hormones. Doxepin may form dangerous combinations with rivaroxapine, estrogens, psychotropic drugs, monoamine oxidase inhibitors, and benzodiazepines. For more complete data on doxepin interactions (28 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 147 mg/kg
Intraperitoneal LD50 in rats: 182 mg/kg
Intravenous LD50 in rats: 16 mg/kg
Oral LD50 in mice: 135 mg/kg
For more complete data on the non-human toxicity values of doxepin (out of 7), please visit the HSDB record page.

Toxicological profile of Doxepin hydrochloride is well-established from clinical use. Common side effects include drowsiness, dry mouth, constipation, and dizziness. Serious adverse events include cardiac arrhythmias, seizures, and serotonin syndrome. The compound is contraindicated in patients with glaucoma, urinary retention, or known hypersensitivity. Overdose can be fatal. The safety profile requires careful monitoring.

[1]. http://pdsp.med.unc.edu/pdsp.php.

[2]. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry, 2001. 62(6): p. 453-63.

[3]. AnnemiekVermeeren, etal. Effects of the use of hypnotics on cognition. Progress in brain research vol. 190 (2011): 89-103.

[4]. G Hajak, etal. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. The Journal of clinical psychiatry vol. 62,6 (2001): 453-63.

[5]. Mahsa Gharzi, etal. Effects of different doses of doxepin on passive avoidance learning in rats. Advanced biomedical research vol. 2 66. 30 Jul. 2013.

[6]. Jimei Bu, etal. Mechanism underlying the effects of doxepin on β-amyloid -induced memory impairment in rats. Iran J Basic Med Sci. 2017 Sep;20(9):1044-1049.

Therapeutic Uses
Adrenergic reuptake inhibitor; anxiolytic; tricyclic antidepressant; antipruritic. A dibenzoxazine heptadecane derivative, a psychotropic drug with anxiolytic and antidepressant effects. ...Recommended for the treatment of anxiety and/or depression associated with neurosis, psychosis, alcoholism, and organ disease. /Hydrochloride/
Veterinary use: For relief of itching caused by canine dermatitis. Mild sedation may occur with prolonged treatment or at doses exceeding the recommended dose.
Doxepin is indicated for short-term (up to 8 days) topical treatment of moderate itching in adult patients with eczematous dermatitis (e.g., atopic dermatitis and chronic simple lichen simplex). /US product label contains: Doxepin, Topical/
For more complete data on the therapeutic uses of doxepin (9 of these), please visit the HSDB record page.
Drug Warnings

Doxepin hydrochloride is contraindicated in patients with glaucoma or a tendency for urinary retention. This medication should not be given to patients currently taking monoamine oxidase inhibitors (MAOIs) or who have taken MAOIs within the past two weeks. It may enhance the suppressive effect of alcohol. It is not recommended for pregnant women or children under 12 years of age. The therapeutic effect of hydrochloride takes approximately 2-3 weeks to appear. Therefore, tricyclic antidepressants should never be prescribed as needed. …Slow onset of action may be related to changes in biogenic amine metabolism…/imipramine/ …It is not recommended for use as a hypnotic. Adequate dosage can lead to hangovers and is less effective than traditional hypnotics. Tricyclic Antidepressants A small number of patients may develop physical dependence after abruptly discontinuing high doses of tricyclic antidepressants, manifesting as malaise, chills, runny nose, and muscle aches… imipramine For more complete data on drug warnings for doxepin (25 total), please visit the HSDB records page.

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Pharmacodynamics
Similar to other tricyclic antidepressants, preclinical trials have shown that doxepin reduces brain electrical activity, prolongs hexobarbital-induced sleep, and inhibits avoidance behavior, but does not affect conditioned affective responses. At high doses, it can also produce central nervous system depressive symptoms. Doxepin is known to have antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are most pronounced, thus limiting its efficacy. These effects are particularly pronounced at high doses, where its affinity for H1 histamine receptors decreases and it binds to other receptors. The maximum antidepressant effect of doxepin usually appears two weeks after the start of treatment. However, the sedative effect of doxepin (often used to treat insomnia or anxiety) appears immediately after administration.

Doxepin hydrochloride is a tricyclic antidepressant used for the treatment of depression, anxiety disorders, and insomnia. It is also used at low doses for the treatment of chronic urticaria and insomnia. The compound is available as a generic formulation. It is a valuable tool for studying histamine and serotonin receptor pharmacology.

C19H22CLNO

315.8371

315.138

1229-29-4

Doxepin-d3 hydrochloride;347840-07-7;Doxepin;1668-19-5

667477

White to off-white solid powder

413.3ºC at 760mmHg

187-189°C

121.3ºC

4.87E-07mmHg at 25°C

4.764

0

2

3

21

363

0

CN(C)CC/C=C/1\C2=CC=CC=C2COC3=CC=CC=C31

ODQWQRRAPPTVAG-GZTJUZNOSA-N

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/b17-11+

(3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~316.62 mM)
H2O : ≥ 50 mg/mL (~158.31 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 140 mg/mL (443.26 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)