Rats in pregnancy that were given chlorcyclizine at doses of 30, 60, and 90 mg/kg at the delicate stage of palate development lived until their planned sacrifice on gestation day (GD) 17 or 21. Rats given 60 or 90 mg/kg of chlorcyclizine experienced 7% and 7% body weight loss, respectively, between doses, as well as temporary unfavorable clinical symptoms (rhinorrhea, red perioral material, urogenital staining, and loose stools). 11%. Rats given 30 mg/kg of chlorcyclizine during gestation did not acquire weight at the anticipated dose intervals, but they did not exhibit any negative clinical symptoms. Testing facility-based historical control database (16 studies, n = 380). Rats that are pregnant usually gain between 12 and 15 weeks of body weight [1].

Absorption, Distribution and Excretion
Readily absorbed after oral administration and widely distributed throughout the body. Metabolised by N-demethylation to form norchlorcyclizine and by N-oxidation.
Slowly excreted in the urine; measurable amounts of norchlorcyclizine have been detected in the urine for up to 3 weeks after the cessation of chronic oral administration. About 0.5% of a single dose is excreted in the urine as the N-oxide.
After a single oral dose of 2 mg/kg to 4 subjects, average peak plasma concentrations of about 0.05 mg/L and 0.03 mg/L were attained in 5 h for unchanged drug and norchlorcyclizine, respectively. After oral administration of 50 mg 3 times a day for 6 days, plasma concentrations of norchlorcyclizine of 0.05 to 0.11 mg/L were reported on the first day after the cessation of treatment and plasma concentrations of 0.02 to 0.04 mg/L were found on the 10th day after cessation of treatment [Kuntzman et al. 1973].
...RATS & MAN TREATED WITH CHLORCYCLIZINE EXCRETE CHLORCYCLIZINE N-OXIDE IN URINE. BENZHYDROLPIPERAZINES & THEIR N-DEALKYLATION PRODUCTS ARE DISTRIBUTED IN ALL TISSUES OF RATS & ARE TRANSFERRED TO FETUS.
...NORCHLORCYCLIZINE IS RETAINED IN HUMANS FOR AT LEAST 20 DAYS AFTER TERMINATION /OF CHLORCYCLIZINE/ THERAPY. .../CHLORCYCLIZINE/ GIVES VERY LOW PLASMA LEVELS SINCE.../IT IS/ MARKEDLY LOCALIZED IN TISSUES, PARTICULARLY LUNG.
STIMULATORY EFFECT OF CHRONIC CHLORCYCLIZINE ADMIN ON ITS OWN METAB IN DOGS: ON DAYS 1-7 DAILY ORAL DOSE OF 10 MG/KG RESULTED IN CHLORCYCLIZINE PLASMA LEVELS OF 4.5 PLUS OR MINUS 1.7 MG/L & ONLY TRACE AMT OF NORCHLORCYCLIZINE. /FROM TABLE/
STIMULATORY EFFECT OF CHRONIC CHLORCYCLIZINE ADMIN ON ITS OWN METAB IN DOGS: AFTER 63 DAYS ADMIN OF 15 MG/KG DAILY ORAL DOSE, PLASMA LEVELS OF CHLORCYCLIZINE WERE IN TRACE AMT & 8.3 PLUS OR MINUS 2.0 MG/L OF NORCHLORCYCLIZINE. /FROM TABLE/
For more Absorption, Distribution and Excretion (Complete) data for CHLORCYCLIZINE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
High concentrations of the N-desmethyl metabolite are found in the liver, lungs, kidney, and spleen.
AFTER CHRONIC ADMIN OF...CHLORCYCLIZINE TO RATS, THE TISSUES CONTAINED DRUG METABOLITES, IN WHICH PIPERAZINE RING FISSION BY MULTIPLE OXIDATIVE N-DEALKYLATION HAD OCCURRED TO GIVE A SUBSTITUTED ETHYLENEDIAMINE. ... ACCUM OF N-(P-CHLOROBENZHYDRYL)ETHYLENEDIAMINE WAS FOUND IN RATS, TREATED WITH CHLOROCYCLIZINE.
OXIDATIVE N-DEALKYLATION IS MAIN METAB PATHWAY OF BENZHYDROLPIPERAZINES... /CHLORCYCLIZINE IS/ TRANSFORMED INTO...NORCHLORCYCLIZINE... CHLORCYCLIZINE N-OXIDE DOES NOT LIE ON METAB PATHWAY CONNECTING CHLORCYCLIZINE WITH NORCHLORCYCLIZINE, BUT RATS & MAN TREATED WITH CHLORCYCLIZINE EXCRETE CHLORCYCLIZINE N-OXIDE IN URINE.
YIELDS DEMETHYLCHLORCYCLIZINE IN RAT. /FROM TABLE/

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Biological Half-Life
about 12 h.

Protein Binding
about 85 to 90%.

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Interactions
SEVERAL REVIEWS BRIEFLY MENTIONED THAT ANTIHISTAMINES INTERFERE WITH ANTICOAGULANT THERAPY; HOWEVER, NO DOCUMENTATION WAS PRESENTED, NO CASE REPORTS OF ANTICOAGULATION PROBLEMS CAUSED BY ANTIHISTAMINES HAVE APPEARED. /ANTIHISTAMINES/
TERATOGENICITY OF CHLORCYCLIZINE IN MICE...IS DIMINISHED BY PRE-TREATMENT EITHER WITH SKF 525A /PROADIFEN/ OR WITH PHENOBARBITONE, & MORE THAN ONE BIOTRANSFORMATION MUST BE INVOLVED.
Plocamadine A (1 ug/ml) produced a slow onset, sustained contraction of the guinea-pig isolated ileum. This was insensitive to atropine (1 umol/l) and tetrodotoxin (1 umol/L), but was significantly reduced by H1-histamine receptor antagonists including mepyramine (10 nmol/l), chlorcyclizine (10 nmol/l) and diphenhydramine (0.1 umol/l).
A method to determine whether chlorcyclizine hydrochloride (I) antihistamine activity could be demonstrated when I was applied topically in combo with 0.5% hydrocortisone acetate (Mantadil; II) cream was described. Hydrocortisone 5%, II, and placebo cream were studied in 30 subjects. The data indicated that a wheal and flare reaction induced in the subjects was decr by the I component of the combo. /Chlorcyclizine hydrochloride/

[1]. Effects of the histamine H1 antagonist Chlorcyclizine on rat fetal palate development. Birth Defects Res B Dev Reprod Toxicol. 2010 Dec;89(6):474-84.

1-[(4-chlorophenyl)-phenylmethyl]-4-methylpiperazine is a diarylmethane.
Chlorcyclizine is a first generation phenylpiperazine class antihistamine used to treat urticaria, rhinitis, pruritus, and other allergy symptoms. Chlorcyclizine also has some local anesthetic, anticholinergic, and antiserotonergic properties, and can be used as an antiemetic.
See also: Chlorcyclizine Hydrochloride (has salt form).

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Mechanism of Action
ANTIHISTAMINES ACT AS PHARMACOLOGICAL ANTAGONISTS OF HISTAMINE AT MOST OF HISTAMINE RECEPTOR SITES, ALTHOUGH NOT BY PREVENTING RELEASE OF HISTAMINE. HEPATIC MICROSOMAL ENZYME-INDUCING PROPERTIES OF CHLORCYCLIZINE...HAVE SHORTENED DURATION OF ACTION OF SOME BARBITURATES AS A RESULT OF ENZYME INDUCTION.
H1 antagonists inhibit most response of smooth muscle to histamine. Antagonism of the constrictor action of histamine on respiratory smooth muscle is easily shown or in vitro. ... Within the vascular tree, the H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by H1 receptors on endothelial cells. Residual vasodilatation reflects the involvement of H2 receptors on smooth muscle and can be suppressed only by the concurrent administration of an H2 antagonist. Effects of the histamine antagonists on histamine induced changes in systemic blood pressure parallel these vascular effects. /H1 Antagonists/
H1 antagonists strongly block the action of histamine that results in increased capillary permeability and formation of edema and wheal. /H1 Antagonists/
All H1 antagonists ... can bind to H1 receptors in the CNS ... H1 antagonists can both stimulate and depress the CNS. /H1 Antagonists/
For more Mechanism of Action (Complete) data for CHLORCYCLIZINE (6 total), please visit the HSDB record page.

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Therapeutic Uses
Histamine H1 Antagonists
MILDLY SEDATIVE ANTIHISTAMINIC AGENT WITH PROLONGED ACTION & LOW INCIDENCE OF TOXIC SIDE EFFECTS. CHLORCYCLIZINE HYDROCHLORIDE HAS SLIGHT ANTICHOLINERGIC & ANTISPASMODIC ACTIONS & ENHANCES ACTION OF EPINEPHRINE. IT ALSO HAS SOME LOCAL ANESTHETIC ACTION.

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Drug Warnings
Although the side effects of the H1 antagonists are rarely serious and often disappear with continued therapy, they are sometimes so troublesome that the drug must be withdrawn. /H1 Antagonists/
The side effect with the highest incidence, and the one common to all H1 antagonists other than terfenadine or astemizole, is sedation. ... Concurrent ingestion of alcohol or other CNS depressants produces an additive effect that impairs motor skills. Other untoward reactions referable to central actions include dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors. /H1 Antagonists/
... Frequent side effects involve the digestive tract and include loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea. ... Other side effects that are apparently caused by the antimuscarinic actions of some of the older agents include dryness of the mouth and respiratory passages, sometimes inducing cough, urinary retention or frequency, and dysuria. ... Palpitation, hypotension, headache, tightness of the chest, and tingling and weakness of the hands may also occur with the older agents. /H1 Antagonists/
Drug allergy may develop when H1 antagonists are given orally, but more commonly it results from topical application. Allergic dermatitis is not uncommon; other hypersensitivity reactions include drug fever and photosensitization. /H1 Antagonists/

C18H21CLN2

300.83

300.139

82-93-9

Chlorcyclizine hydrochloride;14362-31-3

2710

Oil

137-145ºC at 0.1-0.15 MM HG

3.552

0

2

3

21

300

0

ClC1C=CC(C(N2CCN(C)CC2)C2C=CC=CC=2)=CC=1

WFNAKBGANONZEQ-UHFFFAOYSA-N

InChI=1S/C18H21ClN2/c1-20-11-13-21(14-12-20)18(15-5-3-2-4-6-15)16-7-9-17(19)10-8-16/h2-10,18H,11-14H2,1H3

1-((4-chlorophenyl)(phenyl)methyl)-4-methylpiperazine

Chlorcyclizine ChlorcyclizineDi-Paralene, Trihistan,Mantadil, Pruresidine, Chlorcyclizine free base

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.)