CysLT1/cysteinyl leukotriene receptor 1

Montelukast (5 μM; 1 hour) prevents cell damage caused by acetaminophen (APAP) [1]. The 30-minute administration of montelukast (0.01-10 μM) inhibits the migration of cells produced by 5-oxo-ETE and modifies the activation of the plasmin-plasminogen system [3]. The 18-hour duration of 10 μM montelukast modifies MMP-9 activity [3].

Montelukast (3 mg/kg; orally administered) shields mice from hepatotoxicity caused by APAP [1]. When administered via a micro-osmotic pump, montelukast (1 mg/kg) inhibits the production of cysteinyl leukotriene (LT) via the CysLT1 receptor and lessens the alterations in airway remodeling that occur in mice treated with OVA. C4, D4, and E4's roles[2]. Increased levels of IL-4 and IL-13 in the BAL fluid of mice treated with OVA can be decreased by administering 1 mg/kg of montelukast using a micro-osmotic pump [2].

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 migration assay [3]
Cell Types: Eosinophils
Tested Concentrations: 0.01-10 μM
Incubation Duration: 30 minutes
Experimental Results: diminished 5-oxo-ETE-induced cell migration.

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Western Blot Analysis[3]
Cell Types: Eosinophils
Tested Concentrations: 10 μM
Incubation Duration: 18 hrs (hours)
Experimental Results: diminished 5-oxo-ETE-promoted MMP-9 secretion.

Animal/Disease Models: C57BL/6J mice (8 weeks old; 22-25 g) induced acute liver injury [1]
Doses: 3 mg/kg
Route of Administration: po (oral gavage) 1 hour after administration of normal saline or APAP
Experimental Results: Serum moderate alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and reduce liver damage.

Absorption, Distribution and Excretion
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.
It has been reported that montelukast and its metabolites are almost exclusively excreted in the bile and into the feces.
The steady-state volume of distribution recorded for montelukast is an average between 8 to 11 litres.
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.
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.
The pharmacokinetics of montelukast are nearly linear at doses of up to 50 mg.
For more Absorption, Distribution and Excretion (Complete) data for MONTELUKAST (15 total), please visit the HSDB record page.

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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 montelukast sulfoxide, Montelukast 1, 2-Diol, 21-Hydroxymontelukast, and 21(S)-Hydroxy Montelukast.

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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.

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...
... 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.
The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, ... on single-dose theophylline plasma concentrations was studied in three separate clinical trials. Montelukast was evaluated at 10 mg once daily (the clinical dosage), 200 mg once daily, and 600 mg (200 mg three times daily). At the clinical dosage, montelukast did not change single-dose theophylline plasma concentration in a clinically important manner. The geometric mean ratios for theophylline area under the plasma concentration versus time curve (AUC0-->infinity ) (0.92) and maximal plasma concentration (Cmax ) (1.04) were well within the predefined and generally accepted bioequivalence range of 0.80 and 1.25. Montelukast decreased theophylline Cmax by 12% and 10%, AUC0-->infinity by 43% and 44%, and elimination half-time by 44% and 39% at 200 mg/d (oral and intravenous, respectively), and at 600 mg/d, montelukast decreased theophylline Cmax by 25%, AUC0-->infinity by 66%, and elimination half-time by 63%. These results show that montelukast at the clinical dosage did not change theophylline pharmacokinetics in a clinically important manner, but at 20- to 60-fold higher dosages, montelukast significantly reduced the theophylline pharmacokinetics parameters; an apparent dosage dependence is suggested.
High aminotransferases and prolonged prothrombin time on entering our liver unit were revealing parenchymal collapse for this 45-year-old obese woman; treatment failure led her to death. Autoimmunity, paracetamol use, alcoholism, and Wilson's disease were all excluded as causes. Because of chronic asthma, she had been receiving a leukotriene receptor antagonist (montelukast) for 5 years before the current presentation; 1 week before onset she had had 1 week of treatment with two dietary supplements for weight control; one of these included Garcinia Cambogia, a possible cause of two recent cases of hepatitis in the USA; in addition, both formulas contained a citrus derivative that interferes cytochrome functions. /The authors/ speculate on a causal relationship between the assumption of the additives and the fatal hepatitis and envisage a synergy between the additives and montelukast, which per se has well been studied as a hepatotoxic drug. Despite the speculative nature of this presentation, /investigators/ believe the warning may serve to focus attention on the uncontrolled escalation of food additives going on /at present/.
... The present case describes an asthmatic patient, who developed severe obstructive symptoms and progressive heart failure after two sequential exposures to montelukast. As the patient exhibited a markedly raised blood eosinophil count with diffuse infiltrates on chest x-ray and signs of myocarditis, Churg-Strauss syndrome (CSS) was suspected. The disease was confirmed by open lung biopsy. The symptoms improved rapidly after administration of high dose immunosuppression with methylprednisolone and cyclophosphamide. This case is noteworthy because the time course of events strongly suggests a direct aetiological role for montelukast in the development of CSS. The pathophysiological mechanism of the association remains unknown.

[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.

Therapeutic Uses
Anti-Asthmatic agents; Leukotriene Antagonists
Montelukast is indicated for prophylaxis and chronic treatment of asthma in adults and pediatric patients 12 months of age and older. /Included in US product label/
Montelukast is indicated for the relief of symptoms of seasonal allergic rhinitis in adults and pediatric patients 2 years of age and older. /Included in US product label/
Montelukast is not indicated for treatment of bronchospasm in acute asthma attacks, including status asthmaticus. /Not included in US product label/

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Drug Warnings
Headache is the most frequently reported adverse effect with montelukast, occurring in 18-19% of children 6 years of age or older, adolescents, and adults. Headache has been reported in at least 2% of children 2-8 years of age with asthma receiving montelukast and in at least 1% (and more frequently than with placebo) of adults and adolescents 15 years of age or older with asthma. Sinus headache has been reported in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast and more frequently than in those receiving placebo. Dizziness or asthenia/fatigue has occurred in about 1.8-1.9% of patients 15 years of age or older receiving the drug in clinical studies. Dream abnormalities, hallucinations, agitation including aggressive behavior, paresthesia/hypoesthesia, drowsiness, insomnia, irritability, or restlessness also has been reported; seizures have been reported very rarely.
Abdominal pain has occurred in 2.9% of patients 15 years of age or older receiving montelukast. Dyspepsia, infectious gastroenteritis, and dental pain have been reported in 2.1, 1.5, and 1.7% of patients in this age group, respectively. Diarrhea or nausea has been reported in at least 2% of children 6-14 years of age receiving montelukast. Abdominal pain, diarrhea, and gastroenteritis has been reported in at least 2% of children 2-5 years of age with asthma and more frequently than in those receiving placebo. Gastroenteritis has been reported in at least 2% of children 6-8 years of age with asthma and more frequently than in those receiving placebo. Nausea, vomiting, dyspepsia, pancreatitis (rarely), and diarrhea also have been reported with montelukast therapy during postmarketing experience.
Elevations in the results of one or more liver function tests have occurred in patients receiving montelukast in clinical studies. Increases in serum ALT (SGPT) or AST (SGOT) concentrations occurred in 2.1 or 1.6%, respectively, of patients 15 years of age or older with asthma receiving montelukast in clinical studies. Increases in ALT occurred in at least 1% of adult and adolescent patients 15 years of age or older with perennial allergic rhinitis receiving montelukast in clinical studies and more frequently than in those receiving placebo. Changes in laboratory values returned to normal despite continuing montelukast therapy or were not directly attributable to drug therapy. Elevations in serum aminotransferase (transaminase) concentrations also have been reported in children 2-14 years of age receiving montelukast, but the incidence of these elevations was similar to that in children receiving placebo. Hepatic eosinophilic infiltration has been reported very rarely through postmarketing experience with montelukast. Hepatocellular injury, cholestatic hepatitis, or mixed-pattern liver injury also has been reported rarely through postmarketing experience with montelukast. Confounding factors were present in most of these patients, such as the concomitant use of other drugs or alcohol or in the presence of coexisting conditions (e.g., other forms of hepatitis).
Rash has occurred in 1.6% of adults and adolescents 15 years of age or older receiving montelukast. Rash, eczema, dermatitis, or urticaria has been reported in at least 2% of children 2-5 years of age receiving the drug. Atopic dermatitis, varicella, and skin infection have been reported in at least 2% of children 6-8 years of age with asthma receiving montelukast and more frequently than in those receiving placebo. Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, urticaria, and rarely hepatic eosinophilic infiltration, have been reported in patients receiving montelukast.
For more Drug Warnings (Complete) data for MONTELUKAST (17 total), please visit the HSDB record page.

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Pharmacodynamics
Montelukast is a leukotriene receptor antagonist that demonstrates a marked affinity and selectivity to the cysteinyl leukotriene receptor type-1 in preference to many other crucial airway receptors like the prostanoid, cholinergic, or beta-adrenergic receptors. As a consequence, the agent can elicit substantial blockage of LTD4 leukotriene-mediated bronchoconstriction with doses as low as 5 mg. Moreover, a placebo-controlled, crossover study (n=12) demonstrated that montelukast is capable of inhibiting early and late phase bronchoconstriction caused by antigen challenge by 75% and 57% respectively. In particular, it has been documented that montelukast can cause bronchodilation as soon as within 2 hours of oral administration. This action can also be additive to the bronchodilation caused by the concomitant use of a beta agonist. Nevertheless, clinical investigations performed with adults 15 years of age and older revealed that no additional clinical benefit is obtained when doses of montelukast greater than 10 mg a day are used. Additionally, in clinical trials with adults and pediatric asthmatic patients aged 6 to 14 years, it was also determined that montelukast can reduce mean peripheral blood eosinophils by about 13% to 15% from baseline in comparison to placebo during double-blind treatment periods. At the same time, in patients aged 15 years and older who were experiencing seasonal allergic rhinitis, the use of montelukast caused a median reduction of 13% in peripheral blood eosinophil counts when compared to placebo as well.

C35H36CLNO3S

586.18

585.21

C, 71.72; H, 6.19; Cl, 6.05; N, 2.39; O, 8.19; S, 5.47

158966-92-8

Montelukast sodium;151767-02-1;Montelukast dicyclohexylamine;577953-88-9;Montelukast-d6;1093746-29-2

5281040

Light yellow to yellow solid

1.3±0.1 g/cm3

750.5±60.0 °C at 760 mmHg

407.7±32.9 °C

0.0±2.6 mmHg at 25°C

1.678

7.8

2

5

12

41

891

1

CC(C)(C1=CC=CC=C1CC[C@H](C2=CC=CC(=C2)/C=C/C3=NC4=C(C=CC(=C4)Cl)C=C3)SCC5(CC5)CC(=O)O)O

UCHDWCPVSPXUMX-TZIWLTJVSA-N

InChI=1S/C35H36ClNO3S/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)/b15-10+/t32-/m1/s1

Cyclopropaneacetic acid, 1-((((1R)-1-(3-((1E)-2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-

MK-476; MK 476; MK0476; Brondilat; Aerokast; 142522-28-9; UNII-MHM278SD3E; MHM278SD3E; trade names Singulair; Monteflo; Lukotas; Lumona

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)

DMSO : ~250 mg/mL (~426.49 mM)

Solubility in Formulation 1: 2.08 mg/mL (3.55 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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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 (Please use freshly prepared in vivo formulations for optimal results.)