- Histamine H₁ receptor (antagonist activity, no IC₅₀/Ki provided)[1,3,12]
- Human Ether-à-go-go-Related Gene (hERG) K⁺ channel (IC₅₀ = 12 nM for blocking IHERG current)[7]
- P2X₇ receptor (allosteric sensitizer, enhances ATP-induced cation entry)[8]

- Antihistamine activity: Clemastine competitively blocks H₁ receptors on effector cells (e.g., vascular endothelium, airway smooth muscle), reducing histamine-mediated vasodilation and bronchoconstriction. This effect was confirmed in isolated guinea pig tracheal strips and rat mesenteric artery assays[3,12]
- hERG channel inhibition: In HEK293 cells expressing hERG channels, clemastine (12 nM) significantly reduced peak IHERG current by ~50%, with voltage-dependent binding to the channel pore cavity. Mutations Y652A/F656A in the S6 helix attenuated this effect[7]
- P2X₇ receptor modulation: In HEK293 cells stably expressing P2X₇ receptors, clemastine (1-10 μM) enhanced ATP-induced Ca²⁺ influx, accelerated pore dilation (Yo-Pro-1 uptake), and increased fractional permeability to NMDG⁺. Similar effects were observed in human monocyte-derived macrophages and murine bone marrow-derived macrophages[8]
- Autophagy promotion: In LPS-stimulated H9c2 cardiomyocytes, clemastine (10-50 μM) increased LC3-II/LC3-I ratio, Beclin-1 expression, and autophagosome formation, which was abolished by the autophagy inhibitor 3-methyladenine[11]

- Allergic rhinitis model: Oral clemastine (1 mg) administered 4-6 hours before allergen challenge significantly reduced sneezing frequency (p < 0.01) and rhinorrhea severity in 20 allergic subjects. The effect was dose-dependent and lasted ≥12 hours[6]
- Sepsis-induced myocardial injury: In CLP-induced septic rats, intraperitoneal clemastine (30-50 mg/kg) improved 7-day survival rate (from 30% to 60%), reduced serum cTnI levels, preserved left ventricular ejection fraction, and attenuated mitochondrial fragmentation. Similar protective effects were observed in LPS-stimulated H9c2 cells[11]
- Optic neuritis model: Oral clemastine (1 mg twice daily for 90 days) in 16 patients with acute optic neuritis preserved retinal nerve fiber layer (RNFL) thickness in temporal/superotemporal quadrants and enhanced P100 wave amplitude recovery in visual evoked potentials compared to placebo[10]

- hERG channel electrophysiology: Whole-cell patch-clamp recordings were performed on HEK293 cells expressing hERG channels. Cells were perfused with clemastine (1-100 nM) in Tyrode's solution at 37°C. IHERG tail currents were measured at -40 mV after depolarization to +20 mV. IC₅₀ was calculated using nonlinear regression[7]
- P2X₇ receptor calcium flux assay: HEK293-P2X₇ cells were loaded with Fluo-4 AM and treated with clemastine (1-10 μM) followed by ATP (100 μM). Calcium transients were recorded using fluorescence microscopy. Yo-Pro-1 uptake was quantified by flow cytometry to assess pore formation[8]

H₁ receptor antagonism assay: Guinea pig tracheal ring segments were incubated with clemastine (0.1-10 μM) and challenged with histamine (1 μM). Isometric tension changes were recorded to determine antagonist potency[3,12]
- Autophagy detection: H9c2 cardiomyocytes were treated with clemastine (10-50 μM) and LPS (1 μg/mL). LC3-II/LC3-I ratio and Beclin-1 expression were analyzed by Western blot. Autophagosomes were visualized by transmission electron microscopy[11]

- Sepsis model: Male Sprague-Dawley rats (250-300 g) underwent cecal ligation and puncture (CLP). Clemastine (10-50 mg/kg) was dissolved in 0.9% saline and administered intraperitoneally 30 minutes post-CLP. Survival was monitored for 7 days, and cardiac function was assessed by echocardiography on day 3[11]
- Allergic rhinitis model: Human subjects received oral clemastine (1 mg) or placebo in a double-blind crossover design. Nasal allergen challenges were performed 1, 4, and 6 hours post-dose. Sneeze counts and nasal secretion weights were recorded[6]

Absorption, Distribution and Excretion
Rapidly absorbed from the gastrointestinal tract.
Urinary excretion is the major mode of elimination.

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Metabolism / Metabolites
Antihistamines appear to be metabolized in the liver chiefly via mono- and didemethylation and glucuronide conjugation.

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- Absorption: Rapid oral absorption with ~40% bioavailability. Peak plasma concentration (Cmax) of 1-2 ng/mL occurs within 2-4 hours[12]
- Distribution: Extensive tissue distribution (volume of distribution ~800 L), crosses blood-brain barrier. Plasma protein binding ~95%[12]
- Metabolism: Extensively metabolized in liver via O-dealkylation, oxidation, and glucuronidation. Major metabolites include desmethylclemastine and hydroxylated derivatives[12]
- Excretion: ~42% excreted in urine (primarily as metabolites), 27% in feces. Terminal half-life ~21 hours[12]

Hepatotoxicity
Despite widespread use, the first generation antihistamines such as clemastine have rarely been linked to liver test abnormalities or to clinically apparent liver injury. The reason for their safety may relate to low daily dose and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small occasional doses of clemastine are acceptable during breastfeeding. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug. The nonsedating antihistamines are preferred alternatives.
◉ Effects in Breastfed Infants
A 10-week-old breastfed infant whose mother was taking clemastine, phenytoin and carbamazepine was drowsy, refused to feed, was irritable, and had high-pitched crying. These side effects were possibly caused by clemastine in breastmilk, but the other drugs could also have contributed.
In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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- Acute toxicity: LD₅₀ in mice >100 mg/kg (oral). Common adverse effects include sedation, dry mouth, blurred vision, and urinary retention due to anticholinergic activity[12]
- Cardiotoxicity: At supra-therapeutic concentrations (≥1 μM), clemastine prolongs QT interval in isolated feline hearts, but no clinical QT prolongation reported at therapeutic doses (1-6 mg/day)[7,12]
- Drug interactions: Potentiates CNS depression with alcohol, opioids, or benzodiazepines. Contraindicated with MAO inhibitors due to risk of hypertensive crisis[12]

[1]. Mol Pharmacol. 1992 Aug;42(2):227-34.

[2]. Cell Immunol. 1983 Oct 1;81(1):45-60.

[3]. J Pharmacol Exp Ther. 1997 Jan;280(1):114-21.

[4].J Mol Cell Cardiol. 2006 Jan;40(1):107-18.

[5]. J Biol Chem. 2011 Apr 1;286(13):11067-81.

[6]. J Pharmacol Exp Ther. 1997 Jan;280(1):114-21.

[7]. Preprint from Research Square, 29 Jun 2020

[8]. Bioengineered. 2022 Mar;13(3):7134-7146.

[9]. Clemastine. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; January 16, 2017.

Clemastine is 2-[(2R)-1-Methylpyrrolidin-2-yl]ethanol in which the hydrogen of the hydroxy group is substituted by a 1-(4-chlorophenyl)-1-phenylethyl group (R configuration). An antihistamine with antimuscarinic and moderate sedative properties, it is used as its fumarate salt for the symptomatic relief of allergic conditions such as rhinitis, urticaria, conjunctivitis and in pruritic (severe itching) skin conditions. It has a role as a H1-receptor antagonist, an anti-allergic agent, a muscarinic antagonist and an antipruritic drug. It is a N-alkylpyrrolidine and a member of monochlorobenzenes.
An ethanolamine-derivative, first generation histamine H1 antagonist used in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
Clemastine is a first generation antihistamine that is used for symptoms of allergic rhinitis and the common cold. Clemastine has not been linked to instances of clinically apparent acute liver injury.
Clemastine is a synthetic ethanolamine, with anticholinergic, sedative, and histamine H1 antagonistic activities. Upon administration, clemastine blocks the H1 histamine receptor and prevents the symptoms that are caused by histamine activity on capillaries, bronchial and gastrointestinal smooth muscles, including vasodilation, increased capillary permeability, bronchoconstriction, and spasmodic contraction of gastrointestinal smooth muscles. Clemastine also prevents histamine-induced pain and itching of mucous membranes.
A histamine H1 antagonist used as the hydrogen fumarate in hay fever, rhinitis, allergic skin conditions, and pruritus. It causes drowsiness.
See also: Clemastine Fumarate (has salt form).

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Drug Indication
For the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus and acrimation. Also for the management of mild, uncomplicated allergic skin manifestations of urticaria and angioedema. Used as self-medication for temporary relief of symptoms associated with the common cold.

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Mechanism of Action
Clemastine is a selective histamine H1 antagonist and binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine.

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- Mechanism of action: Antihistamine effects via H₁ receptor blockade; cardiotoxicity linked to hERG channel inhibition; neuroprotective effects in optic neuritis may involve autophagy induction and anti-inflammatory pathways[6,7,10,11]
- Therapeutic uses: Approved for allergic rhinitis, urticaria, and pruritus. Investigational use in sepsis-induced myocardial injury and optic neuritis[6,10,11]
- FDA status: Available over-the-counter (1 mg tablets) and by prescription (2 mg tablets). Pregnancy category B[12]

C21H26CLNO

343.895

343.17

C, 73.35; H, 7.62; Cl, 10.31; N, 4.07; O, 4.65

15686-51-8

Clemastine fumarate;14976-57-9

26987

White to off-white solid powder

1.097 g/cm3

425.2ºC at 760mmHg

211ºC

1.553

5.042

0

2

6

24

376

2

C[C@@](C1=CC=CC=C1)(C2=CC=C(C=C2)Cl)OCC[C@H]3CCCN3C

YNNUSGIPVFPVBX-NHCUHLMSSA-N

InChI=1S/C21H26ClNO/c1-21(17-7-4-3-5-8-17,18-10-12-19(22)13-11-18)24-16-14-20-9-6-15-23(20)2/h3-5,7-8,10-13,20H,6,9,14-16H2,1-2H3/t20-,21-/m1/s1

(2R)-2-[2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine

Clemastine; HS-592; clemastine; 15686-51-8; Meclastin; Mecloprodin; Clemastina; HS592; Clemastinum; HS 592

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.)