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Levocetirizine or (R)-Cetirizine, is the levorotary or R-enantiomer of cetirizine, and is a third-generation peripheral H1-receptor antagonist. Levocetirizine is an antihistaminic agent with a higher affinity for the histamine H1-receptor than (S)-Cetirizine. It can effectively treat allergic rhinitis and chronic idiopathic urticaria.
| Targets |
Histamine H1-receptor
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|---|---|
| ln Vitro |
Eosinophils are well known to play essential roles in the development and maintenance of allergic diseases. However, the influence of histamine H1 receptor antagonists on eosinophil functions, especially chemokine production, are not well-defined. Therefore, in the present study, we examined the influence of histamine H1 receptor antagonist on chemokine production by eosinophils through the use of levocetirizine in vitro and in vivo. Eosinophils prepared from mice were stimulated with specific antigens in the presence of different concentrations of levocetirizine. After 24 h, regulated on activation normal T cell expressed and secreted (RANTES) and eotaxin levels in culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Patients with Japanese cedar pollinosis were treated with 5 mg levocetirizine once a day for four weeks during the pollen season (February 2012 to April 2012). RANTES and eotaxin levels in nasal secretions were also examined by ELISA. The addition of levocetirizine to eosinophil cultures caused a dose-dependent decrease in the ability of cells to produce RANTES and eotaxin in response to antigen stimulation, and the minimum concentration that caused a significant decrease was 0.05 μM. Although cetirizine also exerted suppressive effects on the production of RANTES and eotaxin by eosinophils, the minimum concentration that caused significant suppression was 0.15 μM, which was three-times higher than that of levocetirizine. Oral administration of levocetirizine for four weeks also reduced RANTES and eotaxin levels in nasal secretions from patients with pollinosis, along with attenuation of clinical symptoms. The ability of levocetirizine to reduce RANTES and eotaxin levels may account, at least in part, for the clinical efficacy of the agent for allergic disorders, including allergic rhinitis[2].
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| ln Vivo |
Levocetirizine (0.4 mg/kg; oral; male Sprague-Dawley rats) treatment revealed Cmax, AUC0-t, AUC0-∞, and t1/2 of 0.34 μg/mL, 3.26 μg h/mL, and 3.67 μg, respectively. h/mL in Sprague-Dawley rats and 2.34 hours respectively [1].
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| Enzyme Assay |
Assay for transcription factor activation. NF-κB activity in cultured eosinophils was analyzed by commercially available NF-κB ELISA test kits that contained sufficient reagents and a monoclonal antibody against p65, according to the manufacturer's recommendations. In brief, nuclear extract (5.0 mg of protein) from eosinophils was introduced into each well of 96-well microplates precoated with oligonucleotide containing NF-κB consensus site (5’-GGGACTTTCC-3’) in a volume of 20.0 μl, followed by incubation for one hour at 25°C. After washing three times, 100 μl of monoclonal antibody against p65 was added to the appropriate wells and incubated for a further one hour at 25°C. Anti-IgE horseradish peroxidase (HRP) conjugate in a volume of 100 μl was then added and the plates incubated for a further one hour at 25°C. The absorbance at 450 nm was measured after the addition of tetramethylbenzidine (TMB) solution. AP-1 activity was also measured with commercially available AP-1 ELISA test kit in a similar manner[2].
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| Cell Assay |
Assay for mRNA expression. Poly A+ mRNA was separated from cultured cells with oligo(dT)-coated magnetic micro beads. The first-strand cDNA was synthesized from 1.0 mg of PolyA+ mRNA using a Superscript cDNA synthesis kit according to the manufacturer's instructions. Polymerase chain reaction (PCR) was then carried out using a GeneAmp 5700 Sequence Detection Syste. The PCR mixture consisted of 2.0 μl of sample cDNA solution (100 ng/μl), 25.0 μl of SYBR-Green Mastermix, 0.3 μl of both sense and antisense primers, and distilled water to give a final volume of 50.0 μl. The reaction was conducted as follows: 4 min at 94°C, followed by 40 cycles of 15 s at 95°C and 60 s at 60°C. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was amplified as an internal control. mRNA levels were calculated by using the comparative parameter threshold cycle and normalized for GAPDH. The nucleotide sequences of the primers were as follows: for RANTES, 5’-CCTCACCATCATCCTCACTGCA-3’ (sense) and 5’-TCTTCTCTGGGTTGGCACACAC-3’ (antisense), for eotaxin, 5’-CCCTTTTCTGTTCTGCTGACAAG-3’ (sense) and 5’-GAAGAGTCCCTCGATGTGGCTA-3’ (antisense), and for GAPDH, 5’-GTCTTCTGGGTGGCAGTGAT-3’ (sense) and 5’-CCCTTT TCTGTTCTGCTGACAAG-3’ (antisense)[2].
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| Animal Protocol |
Animal/Disease Models: 30 male SD (SD (Sprague-Dawley)) rats (8 weeks old; 200-250 g) [1]
Doses: 0.4 mg/kg Route of Administration: Oral (pharmacokinetic/PK/PK analysis) Experimental Results: Cmax, AUC0-t, AUC0-∞ and t1 /2 were 0.34μg/mL, 3.26μg·h/mL, 3.67μg·h/mL and 2.34 hrs (hrs (hours)) respectively. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following a 5mg oral dose of levocetirizine, a Cmax of 0.27±0.04µg/mL with a Tmax of 0.75±0.50h. The AUC of levocetirizine is 2.31±0.50µg\*h/mL. Taking levocetirizine with food does not affect the AUC but delays Tmax by 1.25 hours and lowers Cmax by 36%. 168 hours post dose an average of 85.4% of a radiolabeled dose was recovered with an average of 80.8% in the urine and 9.5% in the feces. In the urine, 77% of the dose was recovered as unchanged drug, 0.5% as the M8 and M9 metabolites, 0.4% as the M10a metabolite, 0.4% as the M10b metabolite, 0.3% as the M3 metabolite, 0.3% as the M4 and M5 metabolite, 0.2% as the M2 metabolite, and 0.1% as the M1 metabolite. In the feces, 9.0% of the dose was recovered as unchanged drug, 1.0% as the M4 and M5 metabolite, and 0.1% as the M1 metabolite. The volume of distribution of levocetirizine is 0.33±0.02L/kg. The average clearance of levocetirizine is 0.57±0.18mL/min/kg. Metabolism / Metabolites Levocetirizine is poorly metabolized with 85.8% of an oral dose being excreted as the unchanged drug. Levocetirizine can be metabolized to a dihydrodiol (M2), an N-oxide (M3), a hydroxymethoxy derivative (M4), a hydroxy derivative (M5), an O-dealkylated derivative (M6), a taurine conjugate (M8), and an N-dealkylated and aromatic hydroxylated derivative (M9). The M5 metabolite can be glucuronidated to form the M1 metabolite and the M9 metabolite can form 4-chloro-4'-hydroxybenzhydryl mercapturates (M10a and M10b). Biological Half-Life The average half life of levocetirizine is 7.05±1.54 hours. |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation Levocetirizine is the R-enantiomer of cetirizine. Based on limited information from cetirizine and levocetirizine, levocetirizine appears to be 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. International guidelines recommend cetirizine, the racemic form of the drug, as an acceptable choice if an antihistamine is required during breastfeeding. ◉ Effects in Breastfed Infants Relevant published information on levocetirizine was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms in 10% of infants exposed to various antihistamines, and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention. A nursing mother taking levocetirizine 5 mg daily reported no adverse effects in her breastfed infant. ◉ 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 levocetirizine 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. Protein Binding Plasma protein binding of levocetirizine was on average 96.1% 1 hour post dose and 91.9% 6 hours post dose. |
| References | |
| Additional Infomation |
2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid is a diarylmethane.
Levocetirizine is a selective histamine H1 antagonist used to treat a variety of allergic symptoms. It is the R enantiomer of [cetirizine]. Levocetirizine has greater affinity for the histamine H1 receptor than cetirizine. Levocetirizine was granted FDA approval in 1995. Levocetirizine is a Histamine-1 Receptor Antagonist. The mechanism of action of levocetirizine is as a Histamine H1 Receptor Antagonist. Levocetirizine is a third generation, non-sedating, selective histamine H1 receptor antagonist, with antihistamine, anti-inflammatory and potential anti-angiogenic activities. Levocetirizine competes with endogenous histamine for binding at peripheral H1-receptor sites on the effector cell surface. This prevents the negative symptoms associated with histamine release and an allergic reaction. In addition, as histamine plays an important role in angiogenesis during an allergic inflammatory reaction, blocking the action of histamine may modulate the expression of proangiogenic factors and thus may prevent angiogenesis. As a third-generation histamine H1 receptor antagonist, levocetirizine has fewer side effects than most second-generation antihistamines. See also: Levocetirizine Dihydrochloride (has salt form); Cetirizine (annotation moved to). Drug Indication Levocetirizine is indicated to treat symptoms of perennial allergic rhinitis and uncomplicated skin manifestations of chronic idiopathic urticaria. It is also used over the counter for a variety of mild allergy symptoms. FDA Label Mechanism of Action Levocetirizine selectively inhibits histamine H1 receptors. This action prevents histamine from activating this receptor and causing effects like smooth muscle contraction, increased permeability of vascular endothelium, histidine uptake in basophils, stimulation of cough receptors, and stimulation of flare responses in the nervous system. |
| Molecular Formula |
C21H25N2O3CL
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|---|---|
| Molecular Weight |
388.8878
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| Exact Mass |
388.155
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| Elemental Analysis |
C, 64.86; H, 6.48; Cl, 9.12; N, 7.20; O, 12.34
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| CAS # |
130018-77-8
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| Related CAS # |
Cetirizine;83881-51-0;Cetirizine dihydrochloride;83881-52-1;Cetirizine-d4;1219803-84-5;Cetirizine-d8;774596-22-4;Levocetirizine dihydrochloride;130018-87-0;Cetirizine-d4 dihydrochloride;Cetirizine-d8 dihydrochloride;2070015-04-0;Levocetirizine-d4 dihydrochloride;Levocetirizine-d4;1133210-23-7
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| PubChem CID |
1549000
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
542.1±45.0 °C at 760 mmHg
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| Melting Point |
205-208°C (dec.)
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| Flash Point |
281.6±28.7 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.589
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| LogP |
2.16
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
27
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| Complexity |
443
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC=C(C=C1)[C@H](C2=CC=C(C=C2)Cl)N3CCN(CC3)CCOCC(=O)O
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| InChi Key |
ZKLPARSLTMPFCP-OAQYLSRUSA-N
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| InChi Code |
InChI=1S/C21H25ClN2O3/c22-19-8-6-18(7-9-19)21(17-4-2-1-3-5-17)24-12-10-23(11-13-24)14-15-27-16-20(25)26/h1-9,21H,10-16H2,(H,25,26)/t21-/m1/s1
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| Chemical Name |
Acetic acid, (2-(4-((R)-(4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)-
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| HS Tariff Code |
2934.99.9001
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| Storage |
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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~257.14 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.43 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.43 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 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5714 mL | 12.8571 mL | 25.7142 mL | |
| 5 mM | 0.5143 mL | 2.5714 mL | 5.1428 mL | |
| 10 mM | 0.2571 mL | 1.2857 mL | 2.5714 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01567501 | Completed | Drug: Levocetirizine Dihydrochloride tablets 5 mg Drug: Levocetirizine Dihydrochloride |
Fed | IPCA Laboratories Ltd. | 2012-02 | Phase 1 |
| NCT01563081 | Completed | Drug: Levocetirizine Drug: Levocetirizine |
Rhinitis | GlaxoSmithKline | 2012-04 | Phase 3 |
| NCT01000792 | Completed | Drug: Levocetirizine Drug: Levocetirizine |
Allergic Rhinitis | Clinical Research International Limited | 2009-11 | Phase 3 |
| NCT01640535 | Completed | Drug: Montelukast + Levocetirizine Drug: Levocetirizine Drug: Montelukast |
Perennial Allergic Rhinitis | Hanmi Pharmaceutical Company Limited | 2012-06 | Phase 3 |
| NCT03555890 | Completed | Drug: Levocetirizine IRT 5 mg Drug: Levocetirizine ODT 5 mg |
Rhinitis | GlaxoSmithKline | 2018-05-18 | Phase 1 |
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