H1 Receptor

Absorption, Distribution and Excretion
Easily absorbed via the gastrointestinal tract.
Children clear H1 receptor antagonists faster than adults, while those in patients with severe hepatitis clear them more slowly. /H1 Receptor Antagonists/
H1 receptor antagonists are readily absorbed via the gastrointestinal tract. Peak plasma concentrations are reached within 2 to 3 hours after oral administration… /H1 Receptor Antagonists/
Elimination and metabolic profiles of doxylamine and its N-demethylated metabolites were determined in male and female Fischer 344 rats after oral administration of (14) C-doxylamine succinate (13.3 and 133 mg/kg doses). At a dose of 13.3 mg/kg, the cumulative amounts of conjugated doxylamine metabolites excreted in urine and feces in male and female rats were 44.4 ± 4.2% and 47.3 ± 8.1% of the total recovered dose, respectively. At a dose of 133 mg/kg, the cumulative amounts of conjugated doxylamine metabolites excreted in urine and feces by male and female rats were 55.2 ± 2.6% and 47.9 ± 2.5% of the total recovered dose, respectively. Conjugated doxylamine metabolites were isolated, quantified, and identified, including doxylamine O-glucuronide, N-demethyldoxylamine O-glucuronide, and N,N-didemethyldoxylamine O-glucuronide. Elimination of doxylamine and its metabolites was determined after intravenous injection of 0.7 and 13.3 mg/kg of 14C-succinate doxylamine into adult female rhesus monkeys. Although the total radioactive recovery was the same in both the low-dose and high-dose groups (90.2%), the elimination rate of doxylamine and its demethylated metabolite (demethyldoxylamine) in plasma was slower in the high-dose group. With increasing intravenous doxylamine succinate dose, the excretion of doxylamine metabolites (desmethyldoxylamine and bis-desmethyldoxylamine) in 24-hour urine significantly increased, while the excretion of polar doxylamine metabolites significantly decreased. Plasma clearance of doxylamine, as detected by gas chromatography, was determined in adult female rhesus monkeys after oral administration of 7, 13.3, and 27 mg/kg of Bendectin (doxylamine succinate and pyridoxine hydrochloride, also containing dicyclic amine hydrochloride). Results showed that doxylamine clearance decreased with increasing dose. Statistical evaluation of the oral data, fitted using a single-compartment parallel first-order elimination model and a single-compartment parallel first- and second-order (Michaelis equation) elimination model, indicated that the more complex model incorporating the second-order process best fit the observed elimination data. /Doxylamine succinate/

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Metabolism/Metabolites
Hepatitis.
The doxylamine conjugate metabolites were isolated, quantified, and identified as doxylamine O-glucuronide, N-demethyldoxylamine O-glucuronide, and N,N-didemethyldoxylamine O-glucuronide.
Thermospray mass spectrometry (TSP/MS) was used to analyze the synthetic standards doxylamine N-oxide and pyramine N-oxide, as well as the biologically derived metabolites, yielding (M+H)+ ions for each metabolite. Furthermore, TSP/MS and TSP/MS/MS analyses of cyclohydroxylated N-demethyldoxylamine were reported.
Hepatic metabolism.
Half-life: 10 hours
Biobiological half-life
10 hours
The elimination half-life of this drug in healthy adults is approximately 10 hours.

Toxicity Summary
Like other antihistamines, doxylamine works by competitively inhibiting histamine on H1 receptors. It also has significant sedative and anticholinergic effects. Hepatotoxicity
Although doxylamine has been widely used for decades, no association has been found with abnormal liver function or clinically significant liver injury. Its safety is likely related to its short half-life and limited duration of use. Probability Score: E (Unlikely to cause clinically significant liver injury). References on the safety and potential hepatotoxicity of antihistamines are listed after the "Antihistamines Overview" section. Drug Category: Antihistamines Effects During Pregnancy and Lactation ◉ Overview of Use During Lactation Small, occasional doses of doxylamine are not expected to have any adverse effects on breastfed infants. Higher doses or prolonged use may cause infant drowsiness and other adverse reactions, or reduce milk production, especially when used in combination with sympathomimetic drugs (such as pseudoephedrine) or before lactation is fully established.
◉ Effects on breastfed infants
As of the revision date, no published information was found regarding doxylamine. In a telephone follow-up study, mothers reported irritability and colic in 10% of infants exposed to various antihistamines, and drowsiness in 1.6% of infants. None of these reactions required medical attention.
◉ Effects on lactation and breast milk
Injected relatively high doses of antihistamines can lower basal serum prolactin levels in non-lactating women and early postpartum women. However, pre-administration of antihistamines by postpartum mothers does not affect suckling-induced prolactin secretion. Whether lower oral doses of antihistamines have the same effect on serum prolactin, and whether these effects have any consequences for successful breastfeeding, is currently unknown. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Drug Interactions
Concomitant use may enhance the central nervous system depressant effects of these drugs (alcohol or other central nervous system depressants) or antihistamines; additionally, concomitant use of maprotiline or tricyclic antidepressants may enhance the antihistamine or anticholinergic effects of these drugs. /Antihistamines/
When these drugs (anticholinergic drugs or other drugs with anticholinergic activity) are used concomitantly with antihistamines, the anticholinergic effect may be enhanced; patients should be advised to report gastrointestinal problems promptly, as paralytic ileus may occur with concomitant treatment. /Antihistamines/
Concomitant use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong or enhance the anticholinergic and central nervous system depressant effects of antihistamines; concomitant use is not recommended. /Antihistamines/
Concomitant use of ototoxic drugs with antihistamines may mask ototoxic symptoms such as tinnitus, dizziness, or vertigo. /Antichristants/
For more complete data on doxylamine (7 interactions), please visit the HSDB record page.

[1]. Sjöqvist F, Lasagna L. The hypnotic efficacy of doxylamine. Clin Pharmacol Ther. 1967;8(1):48-54.

[2]. Subcutaneous infiltration of doxylamine on cutaneous analgesia in rats. Pharmacol Rep. 2018;70(3):565-569.

[3]. Jackson CD, Blackwell BN. Subchronic studies of doxylamine in B6C3F1 mice. Fundam Appl Toxicol. 1988;10(2):254-261.

Doxylamine is a clear, colorless liquid. (NTP, 1992)
Doxylamine belongs to the pyridine class of compounds and is a tertiary amine. It has various pharmacological effects, including histamine antagonist, cholinergic antagonist, sedative, antiemetic, H1 receptor antagonist, antihistamine, and antitussive.
Doxylamine is a histamine H1 receptor antagonist with significant sedative effects. It is used to treat allergies and can also be used as an antitussive, antiemetic, and hypnotic. Doxylamine has also been used in veterinary medicine and to treat Parkinson's disease.
Doxylamine is an antihistamine. The mechanism of action of doxylamine is as a histamine receptor antagonist.
Doxylamine is a first-generation antihistamine used to treat symptoms of allergic rhinitis and the common cold, and can also be used as a short-acting sedative. No clinically significant cases of acute liver injury have been found to be associated with doxylamine. Doxylamine is a first-generation ethanolamine drug with anti-inflammatory, sedative, and antihistamine effects. Doxylamine competitively inhibits histamine 1 (H1) receptors, thereby blocking the action of endogenous histamine and inhibiting the release of pro-inflammatory mediators from basophils and mast cells. As an inverse agonist, it binds to and stabilizes the inactive form of the H1 receptor, shifting the H1 receptor homeostasis towards an inactive state. This leads to downregulation of nuclear factor-κB (NF-κB) and its dependent antigen presentation, chemotaxis, and the expression of cell adhesion molecules and pro-inflammatory cytokines. Doxylamine is a histamine H1 receptor antagonist with significant sedative effects. It is used to treat allergies and can be used as an antitussive, antiemetic, and hypnotic. Doxylamine has also been used in veterinary medicine and has been used to treat Parkinson's disease. [PubChem] It is used to treat allergies and can also be used as an antitussive, antiemetic, and hypnotic. Doxylamine has also been used in veterinary medicine and to treat Parkinson's disease.
See also: Doxylamine succinate (in salt form).
Drug Indications
It can be used alone as a short-term sleep aid or in combination with other medications as a nighttime remedy for colds and allergies. It can also be used in combination with vitamin B6 (pyridoxine) to prevent morning sickness in pregnant women.
Mechanism of Action
Like other antihistamines, doxylamine works by competitively inhibiting histamine on H1 receptors. It also has significant sedative and anticholinergic effects.

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Therapeutic Uses
Antihistamines; antiemetics; antitussives; histamine H1 receptor antagonists; non-barbiturate sedatives
Antihistamines may be effective for the following symptoms: allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis caused by inhaled allergens and food, mild, uncomplicated allergic skin manifestations (urticaria and angioedema), improvement and prevention of…blood or plasma reactions…/succinates/
Veterinary use: As with other antihistamines, used to treat stomatitis, laminitis, urticaria, respiratory diseases, bloating and indigestion in cattle; used to treat urticaria and laminitis in horses; used to treat dermatitis, urticaria, motion sickness, and to prevent depigmentation in bluenose dogs. /succinates/
Antihistamines are indicated for the prevention and treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis and allergic conjunctivitis caused by inhaled allergens and food. /Antihistamines; included on the US product label/
For more complete data on the therapeutic uses of doxylamine (of 9), please visit the HSDB record page.

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Drug Warnings
Persons taking antihistamines should be aware of their sedative effects and should avoid driving, flying, or operating dangerous machinery…/Antihistamines/
Veterinarians: The use of antihistamines in the treatment of stomatitis, gangrenous mastitis, endometritis, and toxic congestion is questionable. /Succinates/
As with other antihistamines, doxylamine should not be used in premature or full-term newborns. The safety and efficacy of doxylamine as a nighttime sleep aid in children under 12 years of age have not been established. Furthermore, children using antihistamines as a nighttime sleep aid may experience a paradoxical response of central nervous system excitation rather than sedation more frequently than adults. Because doxylamine can cause significant drowsiness, and this drowsiness can be enhanced by other central nervous system depressants (such as sedatives and tranquilizers), children taking this type of medication should use this antihistamine under the guidance of a physician. As an antihistamine, doxylamine should also be used under the guidance of a physician in children aged 2 to 6 years. This medication is not recommended for children under 2 years of age. Because serious adverse reactions can occur when breastfeeding infants take antihistamines, the importance of this medication to the mother should be weighed to decide whether to discontinue breastfeeding or discontinue doxylamine. For more complete data on doxylamine (11 in total), please visit the HSDB records page.

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Pharmacodynamics
Doxylamine is a commonly used antihistamine and can be used as a sleep aid. This medication can also be used to relieve symptoms of hay fever (allergic rhinitis), urticaria (rash or itching), and other allergic reactions. Doxylamine belongs to the ethanolamine class of antihistamines, and its anti-allergic efficacy far surpasses that of almost all other antihistamines on the market, with the exception of diphenhydramine (Benadryl). It is also the most potent over-the-counter sedative available in the United States, with a sedative effect even superior to many prescription hypnotics. One study found that its sedative effect is even better than that of the barbiturate drug phenobarbital. Doxylamine is also a potent anticholinergic drug.

C17H22N2O

270.3695

270.173

469-21-6

Doxylamine succinate;562-10-7;Doxylamine-d5 succinate;1216840-94-6

3162

LIQ

1.043 g/cm3

364.9ºC at 760 mmHg

25°C

174.5ºC

1.5486 (estimate)

2.923

0

3

6

20

276

0

CC(C1=CC=CC=C1)(C2=CC=CC=N2)OCCN(C)C

HCFDWZZGGLSKEP-UHFFFAOYSA-N

InChI=1S/C17H22N2O/c1-17(20-14-13-19(2)3,15-9-5-4-6-10-15)16-11-7-8-12-18-16/h4-12H,13-14H2,1-3H3

N,N-dimethyl-2-(1-phenyl-1-pyridin-2-ylethoxy)ethanamine

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.)