Male ICR mice (22–28 g) were housed 10 per cage under a 12-h light/dark cycle at 22 ± 2°C. Mice were acclimatized for 1 week before experiments. [1]
- Dimenhydrinate, diphenhydramine hydrochloride, and cocaine were dissolved in physiological saline. 8-Chlorotheophylline was dissolved in physiological saline with slow addition of sodium hydroxide until complete dissolution (final pH 6.9). [1]
- CPP apparatus consisted of two compartments (15 × 15 × 15 cm) with distinct wall colors (white vs. black) and floor textures (smooth vs. textured). A computer-based video-tracking system recorded behavior. [1]
- CPP procedure: Pre-conditioning phase (2 days): mice freely explored both compartments for 15 min; day 2 data were recorded. Conditioning phase (6 days): mice received drug (i.p.) on days 1, 3, 5 and were confined to the less preferred compartment for 40 min; on days 2, 4, 6, they received saline and were confined to the preferred compartment for 40 min. Post-conditioning phase: mice were placed in the central tunnel with doors raised, and time spent in each compartment and locomotor activity were recorded for 15 min. [1]
- Dimenhydrinate was administered at 3, 10, 30 mg/kg (i.p.) immediately before confinement. For combination experiments, dimenhydrinate (3 mg/kg, i.p.) was given 15 min before cocaine (7.5 mg/kg, i.p.), then mice were immediately confined. [1]

Absorption, Distribution and Excretion
The peak plasma concentration (Cmax) of the 50 mg oral film-coated tablets was 72.6 ng/mL, with a time to peak concentration (Tmax) of 2.7 hours. The peak plasma concentration (Cmax) of the 100 mg suppository was 112.2 ng/mL, with a time to peak concentration (Tmax) of 5.3 hours. Diphenhydramine is primarily excreted in the urine. 1-3% of dissociated diphenhydramine is excreted unchanged in the urine, while 64% is excreted as metabolites. The excretion of diphenhydramine has not been fully studied. The volume of distribution of diphenhydramine is 3-4 L/kg. Diphenhydramine (ethanolamine): Duration of action (hours) 4-6. /Excerpt from Table/ H1 receptor antagonists are readily absorbed from both the gastrointestinal tract and parenteral administration sites. After oral administration, it takes effect within 15 to 30 minutes, reaches full effect within 1 hour, and lasts for about 3 to 6 hours, although some drugs have a longer duration of action. /Antihistamines/

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Metabolism/Metabolites
Diphenhydramine is a theanine salt that can be broken down into [diphenhydramine] and [8-chlorotheophylline]. Diphenhydramine can undergo N-glucuronidation via UGT to produce diphenhydramine N-glucuronide; it can also undergo N-demethylation via CYP2D6, CYP1A2, CYP2C9, and CYP2C19 to produce N-demethyldiphenhydramine. N-demethyldiphenhydramine can be N-demethylated again by the above enzymes to produce N,N-didemethyldiphenhydramine, which then undergoes oxidative deamination to produce diphenylmethoxyacetic acid.
Currently, research on the metabolic pathways of various antihistamines is limited to only a few compounds. …The main site of metabolic transformation is the liver. /Antichrist/

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Biological Half-Life
The plasma elimination half-life of diphenhydramine is 5-8 hours.

Hepatotoxicity
Despite its widespread use, dimenhydrinate has not been found to be associated with abnormal liver function or clinically significant liver injury. Its safety may be related to the limited duration of its use. Likelihood Score: E (Unlikely to cause clinically significant liver injury). References regarding the safety and potential hepatotoxicity of antihistamines are listed after the "Antihistamines Overview" section. Drug Category: Antihistamines Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Small, occasional doses of dimenhydrinate are not expected to have any adverse effects on breastfed infants. Larger doses or prolonged use may affect the infant or reduce milk production, especially when used in combination with sympathomimetic drugs such as pseudoephedrine or before lactation is fully established. For many women, a single dose taken at bedtime after the last feeding of the day may be sufficient and minimize any side effects of the drug.
◉ Effects on Breastfed Infants
As of the revised date, no published information was found regarding dimenhydrinate. In a telephone follow-up study, mothers reported that 10% of infants exposed to various antihistamines experienced irritability and colic, and 1.6% reported lethargy. None of these reactions required medical attention. In this study, one in seven infants exposed to dimenhydrinate through breast milk reported irritability.
◉ Effects on Lactation and Breast Milk
Injection of 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 did not affect suckling-induced prolactin secretion. Whether low-dose oral antihistamines have the same effect on serum prolactin levels, and whether changes in prolactin levels affect breastfeeding success, are currently unstudied. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.
A woman developed a dependence on diphenhydramine during her first pregnancy and continued taking 150 mg daily for 3 months while breastfeeding her infant. The infant was healthy except for a febrile seizure at age 2, which was likely unrelated to diphenhydramine. During her second pregnancy, she took 300 mg of diphenhydramine daily and continued breastfeeding for two years.
Protein Binding

Diphenhydramine has a protein binding rate of 70-85% in plasma.
Interactions

Theoretically, chlorpheniramine can block the β-adrenergic blocking effect of propranolol and enhance its quinidine-like effects. ...Antihistamines have similar effects to chlorpheniramine. Other antihistamines include...dimethylamine...
Patients taking antihistamines should be advised to avoid concurrent consumption of alcoholic beverages or other central nervous system depressants.../Antihistamines/

[1]. Assessment of the rewarding effects of dimenhydrinate using the conditioned place preference paradigm in mice. Neurosci Lett. 2010 Feb 26;471(1):38-42.

Dimenhydrinate is a white crystalline powder. (NTP, 1992)
8-Chloro-1,3-dimethyl-7H-purine-2,6-dione 2-(diphenylmethyl)oxy-N,N-dimethylethylamine is a diarylmethane compound.
Dimenhydrinate was first documented in 1949 and patented in 1950. Early research on dimenhydrinate focused primarily on its use as an antihistamine for urticaria; its efficacy in treating motion sickness was discovered incidentally. Dimenhydrinate, also known as β-dimethylaminoethyl anisole 8-chlorotheophylline, is used to prevent nausea, vomiting, and dizziness caused by motion sickness. Dimenhydrinate is a compound preparation of diphenhydramine and 8-chlorotheophylline salts, with diphenhydramine content of 53%-55.5% and 8-chlorotheophylline content of 44%-47%. The antiemetic effect of dimenhydrinate is primarily believed to be due to its antagonism of H1 histamine receptors in the vestibular system, while its excitatory effect is thought to be due to the blocking of adenosine receptors by 8-chlorotheophylline. High doses of dimenhydrinate can induce euphoria, characterized by hallucinations, excitement, motor incoordination, and disorientation. Dimenhydrinate was approved by the U.S. Food and Drug Administration (FDA) on May 31, 1972. Dimenhydrinate is a first-generation antihistamine used to treat or prevent motion sickness or symptoms such as nausea and dizziness. No clinically significant cases of acute liver injury have been found to be associated with dimenhydrinate. Dimenhydrinate is an ethanolamine drug, belonging to the first-generation histamine antagonists, and possesses anti-allergic activity. Dimenhydrinate competitively blocks H1 receptors, thereby preventing the effects of histamine on bronchial smooth muscle, capillaries, and gastrointestinal smooth muscle. This can prevent histamine-induced bronchoconstriction, vasodilation, increased capillary permeability, and gastrointestinal smooth muscle spasms.
This compound preparation contains diphenhydramine and theophylline. It is used to treat vertigo, motion sickness, and pregnancy-related nausea.
See also: Diphenhydramine (with active ingredient). 8-Chlorotheophylline (with active ingredient).
Drug Indications

Diphenhydramine is indicated for the prevention and treatment of nausea, vomiting, or vertigo caused by motion sickness.
Mechanism of Action

Diphenhydramine is a theophylline salt that breaks down into diphenhydramine and 8-chlorotheophylline. While the exact mechanism of action is not fully understood, diphenhydramine is thought to reduce balance disturbances through antimuscarinic action or histamine H1 receptor antagonism. 8-Chlorotheophylline may reduce diphenhydramine-induced drowsiness by blocking adenosine receptors to produce an excitatory effect.
It is important to note that H1 receptor antagonists do not inhibit histamine release. Histamine antagonists promote histamine release. Therefore, the beneficial effects of histamine antagonists are limited to antagonizing the response caused by already released histamine. Antihistamines
Drugs that block histamine receptors belong to a large class of pharmacological antagonists. Their mechanism of action appears to be by occupying "receptor sites" on effector cells, excluding agonist molecules without initiating a response themselves. Normally, this antagonistic effect is competitive and reversible. Antihistamines
…Anthistamines exert their effects by centrally antagonizing acetylcholine (ACH), thus effectively treating motion sickness…Their mechanism of action is by blocking excitatory labyrinthine impulses at cholinergic synapses in the vestibular nucleus region. Antihistamines
…Motion sickness…Stimulation of the vestibular apparatus…and the vestibular-cerebellar-midbrain "integrative vomiting center" and the medullary chemoreceptor trigger zone are involved in some way. /Antihistamines/

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Therapeutic Uses
Antiemetics; Histamine H1 Receptor Antagonists
Inhibition of histamine's effects on capillary permeability and on blood vessels, bronchi, and many other types of smooth muscle is characteristic of H1 receptor antagonists and the basis for their widespread clinical use…/Antihistamines/
The “erythema” component and pruritus in the triple reaction caused by intradermal histamine injection…H1 receptor blockers can inhibit both of these reactions. They have local anesthetic effects…H1 receptor blockers selectively inhibit the stimulatory effects of histamine on adrenal pheochromocytocytes and autonomic ganglion cells. /Antihistamines/
…Efficacy against allergic reactions…depends on the degree to which the symptoms are caused by histamine. …In humans…some phenomena, including edema and pruritus, are well controlled; others, such as hypotension, are poorly controlled; bronchoconstriction…is almost nonexistent. /Antihistamines/
For more complete data on the therapeutic uses of xylene-hexamine (12 in total), please visit the HSDB record page.

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Drug Warnings
See Antihistamines. There is a considerable safety margin between therapeutic doses and the usual lethal dose. However, because the seizure-inducing dose is close to the lethal dose, seizures indicate a poor prognosis. Adults survive a single dose of 2.5–5.0 g. Children…30–60 mg/kg body weight can cause…poisoning. /Antihistamines/
At therapeutic doses, all H1 receptor antagonists cause side effects. …rarely serious and usually disappear…sometimes…the drug must be discontinued. There are some differences between different drugs…significant differences exist in individual subjects… /Antihistamines/
…anticholinergic activity, which can cause dry mouth…and…dysuria and impotence. Some drugs can enhance the response to norepinephrine or stimulate adrenergic nerves and inhibit the response to tyramine…rapid intravenous injection of H1 receptor antagonists can cause a transient drop in blood pressure… /Antihistamines/
H1 receptor antagonists can both excite and inhibit the central nervous system. Central nervous system excitation is a prominent feature of antihistamine poisoning and can lead to seizures, especially in infants. Central nervous system depression is usually a symptom accompanying therapeutic doses. /Anthistamines/
Those taking antihistamines should be aware of their sedative effects and should avoid driving, flying, or operating dangerous machinery... /Anthistamines/

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Pharmacodynamics
Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or dizziness caused by motion sickness. Its duration of action is short, lasting 4-8 hours. Patients should be informed of the possibility of significant drowsiness, avoid alcohol and other sedatives, and exercise extra caution when driving motor vehicles or operating heavy machinery.

C24H28CLN5O3

469.9638

469.188

523-87-5

76005-58-8 (HCl);523-87-5;

10660

White to off-white solid powder

343.7ºC at 760 mmHg

102-107ºC

101.5ºC

2.967

1

5

6

33

509

0

O=C(N1C)N(C)C2=C(NC(Cl)=N2)C1=O.CN(C)CCOC(C3=CC=CC=C3)C4=CC=CC=C4

NFLLKCVHYJRNRH-UHFFFAOYSA-N

InChI=1S/C17H21NO.C7H7ClN4O2/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16;1-11-4-3(9-6(8)10-4)5(13)12(2)7(11)14/h3-12,17H,13-14H2,1-2H3;1-2H3,(H,9,10)

2-benzhydryloxy-N,N-dimethylethanamine;8-chloro-1,3-dimethyl-7H-purine-2,6-dione

NSC-117855 NSC117855 NSC 117855 DramalenDimenhydrinate Dramamin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ≥ 37 mg/mL (~78.73 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.43 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 20.8 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: ≥ 2.08 mg/mL (4.43 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 20.8 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: ≥ 2.08 mg/mL (4.43 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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