Doxepin's protective effect is associated with increased PSD-95 and synaptophysin 1 expression via PI3K/AKT/mTOR signaling [6].

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].

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.

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.

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]. 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 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.

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.)