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
Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. 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.
The elimination profile of doxepin is presented as biphasic. 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.
The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg.
The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg.
/DOXEPIN HAS/...A PECULIAR AFFINITY FOR UVEAL MELANIN...ALSO...BOUND BY OCULAR MELANIN BOTH IN VIVO & IN VITRO.
AFTER HUMAN ORAL DOSE 75 MG DOXEPIN-HCL, EST 1ST-PASS METAB RANGED FROM 55-87% OF ORAL DOSE ASSUMING COMPLETE ABSORPTION.
The pharmacokinetics of doxepin have not been extensively studied, but the drug is well absorbed from the GI tract in animals. Peak plasma concentrations occur within 2 hours after oral administration of the drug.
Limited data indicate that doxepin and its active N-demethylated metabolite are distributed into milk in concentrations reportedly ranging from about 30-140% and 10-115%, respectively, of those in maternal serum and that substantial concentrations of the active metabolite have been detected in the serum and urine of nursing infants whose mothers were receiving 75-150 mg daily.

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Metabolism / Metabolites
Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. 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.
AFTER ORAL DOSING OF DOXEPIN-HCL TO HUMANS, METABOLITE DESMETHYLDOXEPIN WAS PRODUCED.
Doxepin has known human metabolites that include Doxepin N-glucuronide.

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Biological Half-Life
The mean elimination half-life is reported to be of 15 hours.
AFTER ORAL 75 MG DOXEPIN-HCL TO HUMANS, PEAK PLASMA CONCN 8.8-45.8 NG/ML, REACHED WITHIN 4 HR. DISAPPEARANCE OF DOXEPIN WAS BIPHASIC & FOLLOWED 1ST-ORDER KINETICS. MEAN DOXEPIN T/2 WAS 16.8 HR. MEAN APPARENT VOL OF DISTRIBUTION WAS 20.2 L/KG.

Interactions
/DOXEPIN/...MAY...POTENTIATE THE DEPRESSANT EFFECT OF ALCOHOL. /HYDROCHLORIDE/
INHIBITION OF THE ANTIHYPERTENSIVE EFFECT OF GUANETHIDINE CAN OCCUR WITH DOSES OF 200-300 MG/DAY. /HYDROCHLORIDE/
DOXEPIN MAY POTENTIATE ORAL ANTICOAGULANTS, AMPHETAMINES, OTHER ANTICHOLINERGICS, MEPROBAMATE, PHENOTHIAZINES, THIOXANTHENE TRANQUILIZERS. DOXEPIN MAY ANTAGONIZE PROPRANOLOL /THEORETICALLY/, METHYLDOPA. DOXEPIN MAY BE ANTAGONIZED BY BARBITURATES. DOXEPIN MAY BE POTENTIATED BY THYROID PREPN.
DOXEPIN MAY FORM HAZARDOUS COMBINATIONS WITH RESERPINE, ESTROGENS, PSYCHOTROPICS, MAO INHIBITORS, BENZODIAZEPINES.
For more Interactions (Complete) data for DOXEPIN (28 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 147 mg/kg
LD50 Rat ip 182 mg/kg
LD50 Rat iv 16 mg/kg
LD50 Mouse oral 135 mg/kg
For more Non-Human Toxicity Values (Complete) data for DOXEPIN (7 total), 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 Uptake Inhibitors; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Antipruritics
A DIBENZOXEPIN DERIVATIVE THAT IS A PSYCHOTHERAPEUTIC AGENT WITH ANTIANXIETY & ANTIDEPRESSANT PROPERTIES. ...RECOMMENDED FOR MGMNT OF ANXIETY &/OR DEPRESSIVE STATES ASSOCIATED WITH PSYCHONEUROSIS, PSYCHOSIS, ALCOHOLISM, & ORG DISEASE. /HYDROCHLORIDE/
VET: FOR RELIEF OF PRURITIS IN DERMATOSES IN DOGS. MILD TRANQUILIZING EFFECT IS NOTED AFTER PROLONGED THERAPY OR ON DOSES ABOVE THOSE RECOMMENDED.
Doxepin is indicated for the short-term (up to 8 days) topical treatment of moderate pruritus in adult patients with eczematous dermatitis, e.g., atopic dermatitis and lichen simplex chronicus. /Included in US product labeling; Doxepin, topical/
For more Therapeutic Uses (Complete) data for DOXEPIN (9 total), please visit the HSDB record page.

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Drug Warnings
DOXEPIN HYDROCHLORIDE IS CONTRAINDICATED IN PT WITH GLAUCOMA OR TENDENCY TO URINARY RETENTION. ...SHOULD NOT BE ADMIN TO PT EITHER ON MAO INHIBITORS OR WHO HAVE BEEN...WITHIN THE PRIOR 2 WK. ...MAY...POTENTIATE DEPRESSANT EFFECT OF ALCOHOL. USE...IN PREGNANT PT OR...CHILDREN UNDER 12...NOT RECOMMENDED. /HYDROCHLORIDE/
ABOUT 2-3 WK MUST PASS BEFORE THERAPEUTIC EFFECTS...ARE EVIDENT. FOR THIS REASON, TRICYCLIC ANTIDEPRESSANTS SHOULD NEVER BE PRESCRIBED ON AN "AS-NEEDED" BASIS. ...SLOW ONSET OF EFFECTS MAY RELATE TO CHANGES IN METAB OF BIOGENIC AMINES THAT OCCUR... /IMIPRAMINE/
...GENERAL USE FOR HYPNOSIS IS NOT RECOMMENDED. IN ADEQUATE DOSES THEY CAUSE HANGOVER & ARE NOT AS EFFECTIVE AS A CONVENTIONAL HYPNOTIC. /TRICYCLIC ANTIDEPRESSANTS/
OCCASIONAL PT WILL SHOW PHYSICAL DEPENDENCE ON TRICYCLIC ANTIDEPRESSANTS, WITH MALAISE, CHILLS, CORYZA, & MUSCLE ACHING FOLLOWING ABRUPT DISCONTINUATION OF HIGH DOSES... /IMIPRAMINE/
For more Drug Warnings (Complete) data for DOXEPIN (25 total), please visit the HSDB record page.

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Pharmacodynamics
Similar to other tricyclic antidepressants, doxepin was shown, 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. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed 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.)