The augmentation of PSD-95 and synaptophysin 1 expression via the PI3K/AKT/mTOR signaling pathway is linked to the protective effect of doxepin [4].

In rats, Aβ1-42-induced memory impairment can be avoided with doxepin (doxepin intraperitoneally given 1 mg/kg and 5 mg/kg once a day for 21 consecutive days) [4].

Western Blot Analysis[4]
Cell Types: SH-SY5Y human neuroblastoma cell line
Tested Concentrations: 10 ng/mL
Incubation Duration: 2 hrs (hours)
Experimental Results: Increased expression of PSD-95, synaptophysin 1 and p-AKT in SH- protein expression level in SY5Y cells, and diminished the protein expression level of p-mTOR in SH-SY5Y cells.

Animal/Disease Models: SD male rats [4]
Doses: 1, 5mg/kg
Route of Administration: Doxepin (doxepin intraperitoneally (ip) (ip) injected 1mg/kg and 5mg/kg, one time/day for 21 days)
Experimental Results: Improved PSD- Protein expression level After treatment with doxepin at 1 mg/kg, p-AKT protein expression levels diminished in the hippocampus and temporal lobes, and p-AKT protein expression levels diminished in the hippocampus and temporal lobes.

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.

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.

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

[2]. 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.

[3]. Effects of different doses of doxepin on passive avoidance learning in rats. Advanced biomedical research vol. 2 66. 30 Jul. 2013.

[4]. 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.

C19H21NO

279.37614

279.162

1668-19-5

Doxepin Hydrochloride;1229-29-4;Doxepin-d3 hydrochloride;347840-07-7

667477

OILY LIQUID CONSISTING OF A MIXTURE OF CIS- & TRANS- ISOMERS

1.122 g/cm3

413.3ºC at 760 mmHg

187-189ºC

121.3ºC

4.87E-07mmHg at 25°C

1.5000 (estimate)

3.962

0

2

3

21

363

0

CN(C)CCC=C1C2=CC=CC=C2COC3=CC=CC=C13

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

MF 10; Doxepin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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