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Montelukast sodium (also known as MK-476; trade names Singulair; Monteflo; Lukotas; Lumona) is a novel, potent, selective CysLT1 (leukotriene receptor) receptor antagonist used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. Montelukast binds to the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes, blocking the action of leukotriene D4 (as well as secondary ligands LTC4 and LTE4) on this receptor. This lessens inflammation and the bronchoconstriction that the leukotriene would have otherwise produced.
Physicochemical Properties
| Molecular Formula | C35H35CLNNAO3S |
| Molecular Weight | 608.17 |
| Exact Mass | 607.192 |
| Elemental Analysis | C, 69.12; H, 5.80; Cl, 5.83; N, 2.30; Na, 3.78; O, 7.89; S, 5.27 |
| CAS # | 151767-02-1 |
| Related CAS # | Montelukast; 158966-92-8; Montelukast-d6 sodium; 2673270-26-1; Montelukast dicyclohexylamine; 577953-88-9; Montelukast-d6; 1093746-29-2 |
| PubChem CID | 23663996 |
| Appearance | White to off-white solid |
| Boiling Point | 750.5ºC at 760mmHg |
| Melting Point | 115 °C(dec.) |
| Flash Point | 407.7ºC |
| LogP | 7.613 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 12 |
| Heavy Atom Count | 42 |
| Complexity | 898 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | ClC1=CC2=C(C=C1)C=CC(/C=C/C3=CC([C@H](SCC4(CC([O-])=O)CC4)CCC5=CC=CC=C5C(C)(O)C)=CC=C3)=N2.[Na+] |
| InChi Key | LBFBRXGCXUHRJY-HKHDRNBDSA-M |
| InChi Code | InChI=1S/C35H36ClNO3S.Na/c1-34(2,40)30-9-4-3-7-25(30)13-17-32(41-23-35(18-19-35)22-33(38)39)27-8-5-6-24(20-27)10-15-29-16-12-26-11-14-28(36)21-31(26)37-29;/h3-12,14-16,20-21,32,40H,13,17-19,22-23H2,1-2H3,(H,38,39);/q;+1/p-1/b15-10+;/t32-;/m1./s1 |
| Chemical Name | sodium;2-[1-[[(1R)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetate |
| Synonyms | Montelukast sodium; MK-476; MK476; MK 476; MK-0476; MK 0476; MK0476; Montelukast sodium salt; Montair; Kokast; Montelukast sodium [USAN]; Montelukast (sodium); trade names Singulair; Montelo-10; Monteflo; Lukotas; Lumona |
| HS Tariff Code | 2934.99.9001 |
| 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, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | CysLT1/cysteinyl leukotriene receptor 1 |
| ln Vitro |
Montelukast (5 μM; 1 h) prevents cell damage caused by APAP (acetaminophen) (HY-66005)[1]. Montelukast (0.01-10 μM; 30 min) attenuates the plasmin-plasminogen system activation and reduces the 5-oxo-ETE-induced cell migration[3]. Montelukast (10 μM; 18 h) modifies MMP-9 activation[3]. |
| ln Vivo |
Montelukast (3 mg/kg; oral gavage) shields mice's livers from APAP-induced hepatotoxicity[1]. Montelukast (1 mg/kg; miniosmotic pump administration) inhibits the effects of cysteinyl leukotrienes (LT) C4, D4, and E4, which are mediated by the CysLT1 receptor, and lessens the alterations in airway remodeling seen in mice given OVA[2]. Montelukast (1 mg/kg; miniosmotic pump administration) lowers the elevated levels of IL-4 and IL-13 in the BAL fluid of mice treated with OVA[2]. |
| Enzyme Assay | Montelukast and MK-0591 decreased eosinophil migration promoted by 5-oxo-ETE, whereas LTD(4) failed to induce eosinophil migration. However, LTD(4) significantly boosted the migration rate obtained with a suboptimal concentration of 5-oxo-ETE and partially reversed the inhibition obtained with MK-0591. Montelukast significantly reduced the maximal rate of activation of plasminogen into plasmin by eosinophils obtained with 5-oxo-ETE. 5-Oxo-ETE increased the number of eosinophils expressing urokinase plasminogen activator receptor and stimulated secretion of MMP-9. Montelukast, but neither MK-0591 nor LTD(4), reduced the expression of urokinase plasminogen activator receptor and the secretion of MMP-9 and increased total cellular activity of urokinase plasminogen activator and the expression of plasminogen activator inhibitor 2 mRNA [3]. |
| Cell Assay |
Cell Line: Eosinophils Concentration: 0.01-10 μMbr> Incubation Time: 30 minbr> Result: Diminished the 5-oxo-ETE–induced cell migration. Purified blood eosinophils were treated with or without montelukast; MK-0591, a 5-lipoxygenase-activating protein inhibitor; or leukotriene (LT) D(4). Migration assays through Matrigel were performed in the presence of 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemotactic factor, or LTD(4). Expression of molecules implicated in plasmin generation and matrix metalloproteinase (MMP) 9 release were also evaluated. Results: Montelukast and MK-0591 decreased eosinophil migration promoted by 5-oxo-ETE, whereas LTD(4) failed to induce eosinophil migration. However, LTD(4) significantly boosted the migration rate obtained with a suboptimal concentration of 5-oxo-ETE and partially reversed the inhibition obtained with MK-0591. Montelukast significantly reduced the maximal rate of activation of plasminogen into plasmin by eosinophils obtained with 5-oxo-ETE. 5-Oxo-ETE increased the number of eosinophils expressing urokinase plasminogen activator receptor and stimulated secretion of MMP-9. Montelukast, but neither MK-0591 nor LTD(4), reduced the expression of urokinase plasminogen activator receptor and the secretion of MMP-9 and increased total cellular activity of urokinase plasminogen activator and the expression of plasminogen activator inhibitor 2 mRNA. Conclusion: Montelukast inhibits eosinophil protease activity in vitro through a mechanism that might be independent of its antagonist effect on CysLT 1 receptor[3]. |
| Animal Protocol |
C57BL/6J mice (8-week-old; 22-25 g) are induced acute hepatic injury 3 mg/kg Oral gavage 1 h after saline or APAP administration This study used 8-week-old C57BL/6J mice (22–25 g), which were randomly selected for this experimental study. The acute hepatic injury was induced by oral administration of APAP (200 mg/kg) before 16 h fasting as described (Saini et al., 2011; Pu et al., 2016). For therapeutic experiment, a dose of 3 mg/kg (Hamamoto et al., 2017) of Montelukast was prepared in a 0.5% carboxy methyl cellulose. Mice were gavaged in a volume of 100 μl at 1 h after APAP administration. Mice were killed by CO2 at 12 h after APAP administration, and blood and liver tissue were harvested for histology. [1] Female BALB/c mice (aged 6–8 wk) received an intraperitoneal injection of 100 μg of ovalbumin (OVA) complexed with alum on Days 0 and 14. Mice received an intranasal dose of 500 μg OVA on Days 14, 27, 28, 29, 47, 61, 73, 74, and 75. The control group received normal saline with alum intraperitoneally on Days 0 and 14 and saline without alum intranasally on Days 14, 27, 28, 29, 47, 61, 73, 74, and 75. A group of OVA-treated mice was administered the cysteinyl leukotriene1 (CysLT1) receptor antagonist Montelukast sodium (MK-0476) that was dissolved in distilled water containing 10% Na2CO3 (5). Then 200-μl Alzet Model 2004 miniosmotic pumps (6 μl/d delivery rate) containing Montelukast (1 mg/kg) or vehicle control were placed subcutaneously on Day 26 and replaced on Day 54.[2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Absorption It has been observed that montelukast is quickly absorbed following administration by the oral route. The oral bioavailability documented for the drug is 64%. Furthermore, it seems that having a regular meal in the morning or even a high fat snack in the evening does not affect the absorption of montelukast. Route of Elimination It has been reported that montelukast and its metabolites are almost exclusively excreted in the bile and into the feces. Volume of Distribution The steady-state volume of distribution recorded for montelukast is an average between 8 to 11 litres. Clearance The plasma clearance documented for montelukast is an average of 45 mL/min when observed in healthy adults. Montelukast is rapidly absorbed from the GI tract, and peak plasma concentrations are attained within 3-4, 2-2.5, or 2 hours following oral administration in the fasted state of a single 10-mg film-coated (in adults), 5-mg chewable (in adults), or 4-mg chewable (in children 2-5 years of age) tablet, respectively. ... Ingestion of a high-fat meal in the morning with the 4-mg oral granules formulation had no effect on the AUC of montelukast; however, the time to peak plasma concentrations was prolonged from 2.3 hours to 6.4 hours and peak plasma concentrations were reduced by 35%. Absorption /of montelukast is/ rapid. For the 10-mg tablets: mean oral bioavailability is 64%. Bioavailability is not affected by a standard meal in the morning. For the 5-mg chewable tablet: mean oral bioavailability is 73% in the fasted state versus 63% when administered with a standard meal in the morning. View More
Following oral administration of montelukast 10 mg daily for 7 days in fasting young adults, peak plasma concentrations averaged 541 ng/mL on day 1 and 602.8 ng/mL on day 7. Trough concentrations on days 3-7 were essentially constant and ranged from 18-24 ng/mL. In this study, values for area under the plasma concentration-time curve (AUC) at steady-state were about 14-15% higher than those achieved with a single dose, and were reached within 2 days.
Metabolism / Metabolites It has been determined that montelukast is highly metabolized and typically so by the cytochrome P450 3A4, 2C8, and 2C9 isoenzymes. In particular, it seems that the CYP2C8 enzymes play a significant role in the metabolism of the drug. Nevertheless, at therapeutic doses, the plasma concentrations of montelukast metabolites are undetectable at steady state in adults and pediatric patients. Biotransformation /is/ hepatic and extensive involving cytochrome P450 3A4 and 2C9 The metabolic fate of montelukast has not been fully determined, but the drug is extensively metabolized in the GI tract and/or liver and excreted in bile. Several metabolic pathways have been identified including acyl glucuronidation, and oxidation catalyzed by several cytochrome P-450 (CYP) isoenzymes. In vitro studies indicate that the microsomal P-450 isoenzyme CYP3A4 is the major enzyme involved in formation of the 21-hydroxy metabolite (M5) and a sulfoxide metabolite (M2), and CYP2C9 is the major isoenzyme involved in the formation of the 36-hydroxy metabolite (M6). Other identified metabolites include an acyl glucuronide (M1) and a 25-hydroxy (a phenol, M3) analog. Following oral administration of 54.8 mg of radiolabeled montelukast, metabolites of the drug represented less than 2% of circulating radioactivity. Montelukast metabolites that have been identified in plasma in radiolabeled studies include the 21-hydroxy (diastereomers of a benzylic acid, M5a and M5b) and the 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) metabolites. Following oral administration of therapeutic doses of montelukast, plasma concentrations of metabolites at steady-state in adults and children were below the level of detection. Montelukast has known human metabolites that include 21-Hydroxymontelukast, 21(S)-Hydroxy Montelukast, Montelukast 1, 2-Diol, and montelukast sulfoxide. Biological Half-Life Studies have demonstrated that the mean plasma half-life of montelukast varies from 2.7 to 5.5 hours when observed in healthy young adults. The mean plasma elimination half-life of montelukast in adults 19-48 years of age is 2.7-5.5 hours, and plasma clearance averages 45 mL/minute. A plasma elimination half-life of 3.4-4.2 hours has been reported in children 6-14 years of age. Limited data indicate that the plasma elimination half-life of montelukast is prolonged slightly in geriatric adults and in patients with mild to moderate hepatic impairment, although dosage adjustment is not required. A plasma elimination half-life of 6.6 or 7.4 hours has been reported in geriatric adults 65-73 years of age or patients with mild to moderate hepatic impairment, respectively. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In clinical trials, mild elevations in serum aminotransferase levels were found in 1% to 2% of patients taking montelukast chronically, but similar rates are reported in matched placebo recipients. The ALT abnormalities were usually mild, asymptomatic and self limited. Clinically apparent liver injury from montelukast is rare; but more than a dozen cases reported in the literature. In these cases, the latency to onset of injury was highly variable, ranging from a few days to several years. Patients presented with anorexia, nausea, right upper quadrant pain, dark urine, and jaundice. The pattern of enzyme elevation was usually mixed, but both hepatocellular or cholestatic patterns have been reported. Allergic features and autoantibody formation were rare. Eosinophilia was often reported, but this may have been due to the underlying allergic condition rather than the liver injury. The injury usually resolved within 1 to 4 months of stopping the drug. Likelihood score: B (rare but likely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Very low levels of montelukast appear in breastmilk. Montelukast is approved for use in children as young as 6 months of age and has been used in neonates in dosages far greater than the amounts in breastmilk. Amounts ingested by the infant would not be expected to cause any adverse effects in breastfed infants. International guidelines consider that leukotriene receptor antagonists can be used during breastfeeding. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. View More
◈ What is montelukast?
Interactions Concurrent use /of phenobarbital/ results in significant decreases (approximately 40%) in the area under the curve [AUC] for montelukast, of induction of hepatic metabolism... Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2007., p. 2030 ... This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs. Protein Binding It has been determined that the protein binding of montelukast to plasma proteins exceeds 99%. |
| References |
[1]. Montelukast Prevents Mice Against Acetaminophen-Induced Liver Injury. Front Pharmacol. 2019 Sep 18; 10:1070. [2]. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med. 2002 Jan 1; 165(1): 108-16. [3]. Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism. J Allergy Clin Immunol. 2006;118(1):113-119. [4]. Montelukast in hospitalized patients diagnosed with COVID-19. J Asthma. 2022 Apr;59(4):780-786. |
| Additional Infomation |
Montelukast sodium is an organic sodium salt. It contains a montelukast(1-). Montelukast Sodium is the orally bioavailable monosodium salt of montelukast, a selective cysteinyl leukotriene receptor antagonist with anti-inflammatory and bronchodilating activities. Montelukast selectively and competitively blocks the cysteinyl leukotriene 1 (CysLT1) receptor, preventing binding of the inflammatory mediator leukotriene D4 (LTD4). Inhibition of LTD4 activity results in inhibition of leukotriene-mediated inflammatory events including: migration of eosinophils and neutrophils; adhesion of leukocytes to vascular endothelium, monocyte and neutrophil aggregation; increased airway edema; increased capillary permeability; and bronchoconstriction. The CysLT1 receptor is found in a number of tissues including spleen, lung, placenta, small intestine, and nasal mucosa, and in a variety of cell types including monocyte/macrophages, mast cells, eosinophils, CD34-positive hemopoietic progenitor cells, neutrophils and endothelial cells. See also: Montelukast (has active moiety). Drug Indication Asthma |
Solubility Data
| Solubility (In Vitro) |
DMSO: 50~100 mg/mL (82.2~164.4 mM) Water: ~100 mg/mL Ethanol: ~100 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: 1.25 mg/mL (2.06 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6443 mL | 8.2214 mL | 16.4428 mL | |
| 5 mM | 0.3289 mL | 1.6443 mL | 3.2886 mL | |
| 10 mM | 0.1644 mL | 0.8221 mL | 1.6443 mL |