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.

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Model of APAP-Induced Acute Liver Injury:** Eight-week-old C57BL/6J male mice (22-25 g) were fasted for 16 hours prior to APAP administration. Acute hepatic injury was induced by a single oral gavage of APAP (200 mg/kg). For the therapeutic experiment, Montelukast was suspended in 0.5% carboxymethyl cellulose to achieve a dose of 3 mg/kg. One hour after APAP administration, mice were orally gavaged with 100 µL of the Montelukast suspension or vehicle. Mice were euthanized by CO₂ asphyxiation 12 hours after APAP administration. Blood was collected via cardiac puncture for serum isolation, and liver tissues were harvested for histological and biochemical analysis.

Absorption, Distribution and Excretion
Montelukast is observed to be rapidly absorbed after oral administration. The oral bioavailability of this drug is 64%. Furthermore, it appears that normal morning meals or high-fat snacks in the evening do not affect the absorption of montelukast. Montelukast and its metabolites are reported to be excreted almost entirely via bile and feces. The mean steady-state volume of distribution of montelukast is 8 to 11 liters. The mean plasma clearance of montelukast observed in healthy adults is 45 mL/min. Montelukast is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 3–4 hours, 2–2.5 hours, or 2 hours after oral administration of a single 10 mg film-coated tablet (adult), 5 mg chewable tablet (adult), or 4 mg chewable tablet (children aged 2–5 years) on an empty stomach. When taking 4 mg of oral granules in the morning, the intake of a high-fat meal had no effect on the AUC of montelukast; however, the time to peak concentration was prolonged from 2.3 hours to 6.4 hours, and the peak concentration decreased by 35%. Montelukast is rapidly absorbed. The mean oral bioavailability of the 10 mg tablets is 64%. A standard morning meal does not affect its bioavailability. For the 5 mg chewable tablets: the mean oral bioavailability on an empty stomach is 73%, while it is 63% when taken with a standard morning meal. In fasting young adults, after 7 consecutive days of oral administration of 10 mg montelukast, the mean peak plasma concentration was 541 ng/mL on day 1 and 602.8 ng/mL on day 7. The trough concentration remained relatively stable from day 3 to day 7, ranging from 18 to 24 ng/mL. In this study, the steady-state area under the plasma concentration-time curve (AUC) was approximately 14-15% higher than that after a single dose, and was reached within 2 days. Montelukast's pharmacokinetics are nearly linear at doses up to 50 mg. For more complete data on absorption, distribution, and excretion of montelukast (15 items total), please visit the HSDB record page. Metabolism/Metabolites: Montelukast has been identified as actively metabolized, typically by cytochrome P450 3A4, 2C8, and 2C9 isoenzymes. In particular, the CYP2C8 enzyme appears to play a significant role in drug metabolism. However, at therapeutic doses, plasma concentrations of montelukast metabolites are undetectable in both adult and pediatric patients at steady state. Biotransformation occurs primarily in the liver, involving cytochrome P450 3A4 and 2C9. The metabolic pathway of montelukast is not fully understood, but the drug is extensively metabolized in the gastrointestinal tract and/or liver and excreted via bile. Multiple metabolic pathways have been identified, including acylglucuronidation and oxidation catalyzed by various cytochrome P-450 (CYP) isoenzymes. In vitro studies have shown that the microsomal P-450 isoenzyme CYP3A4 is the major enzyme in the formation of the 21-hydroxy metabolite (M5) and the sulfoxide metabolite (M2), while CYP2C9 is the major isoenzyme in the formation of the 36-hydroxy metabolite (M6). Other identified metabolites include acylglucuronide (M1) and 25-hydroxy (phenolic, M3) analogues. Following oral administration of 54.8 mg of radiolabeled montelukast, drug metabolites account for less than 2% of circulating radioactivity. In radiolabeling studies, montelukast metabolites identified in plasma include 21-hydroxy (benzyl acid diastereomers, M5a and M5b) metabolites and 36-hydroxy (methanol diastereomers, M6a and M6b) metabolites. Following oral administration of therapeutic doses of montelukast, steady-state plasma metabolite concentrations in both adults and children were below the limit of detection. Known metabolites of montelukast include montelukast sulfoxide, montelukast 1,2-diol, 21-hydroxymontelukast, and 21(S)-hydroxymontelukast. Biological half-life: Studies have shown that the mean plasma half-life of montelukast in healthy young adults is 2.7 to 5.5 hours. The mean plasma elimination half-life of montelukast in adults aged 19–48 years is 2.7–5.5 hours, with a mean plasma clearance of 45 mL/min. The plasma elimination half-life in children aged 6–14 years is 3.4–4.2 hours. Limited data suggest a slightly prolonged plasma elimination half-life of montelukast in older adults and patients with mild to moderate hepatic impairment, but no dose adjustment is necessary. According to reports, the plasma elimination half-life for elderly people aged 65-73 and patients with mild to moderate liver dysfunction is 6.6 hours and 7.4 hours, respectively.

Interactions
Concomitant use of phenobarbital significantly reduced the area under the concentration-time curve (AUC) of montelukast (approximately 40%) and induced hepatic metabolism… This study aimed to assess whether clinically used dose levels of montelukast interfered 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 day 7 of a 12-day montelukast treatment regimen, or montelukast 10 mg orally daily, or placebo. Montelukast had no significant effect on the AUC and peak plasma concentration of either R- or S-warfarin. However, in the presence of montelukast, a slight but statistically significant reduction in the time to peak concentration of both enantiomers of warfarin and the elimination half-life of the less potent R-warfarin was observed. These changes were considered clinically insignificant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio of prothrombin time (INR) (AUC 0-144 and maximum INR). These results suggest that clinically significant drug interactions are unlikely in patients requiring concomitant administration of these two medications.
The effect of the cysteyl leukotriene receptor antagonist montelukast (MK-0476) on single-dose theophylline plasma concentrations was investigated in three independent clinical trials. The evaluable doses of montelukast were 10 mg once daily (clinical dose), 200 mg once daily, and 600 mg three times daily (200 mg each time). At the clinical dose, montelukast did not produce a clinically significant change in single-dose theophylline plasma concentrations. The geometric mean ratios of the area under the theophylline plasma concentration-time curve (AUC_0-∞) (0.92) and the geometric mean ratios of the maximum plasma concentration (C_max) (1.04) were both within the pre-specified, generally accepted bioequivalence ranges (0.80 and 1.25). Montelukast at a dose of 200 mg/day (oral and intravenous) reduced theophylline's C_max by 12% and 10%, AUC_0-∞ by 43% and 44%, and elimination half-life by 44% and 39%, respectively; at a dose of 600 mg/day, montelukast reduced theophylline's C_max by 25%, AUC_0-∞ by 66%, and elimination half-life by 63%. These results indicate that clinical doses of montelukast do not have a clinically significant effect on the pharmacokinetics of theophylline, but when the dose is increased 20 to 60 times, montelukast significantly reduces theophylline pharmacokinetic parameters, suggesting a clear dose-dependent effect. A 45-year-old obese woman was admitted with elevated transaminase levels and prolonged prothrombin time, indicating liver atrophy; treatment failure led to her death. Autoimmune diseases, acetaminophen use, alcohol poisoning, and Wilson's disease have been ruled out. She had been taking the leukotriene receptor antagonist (montelukast) for 5 years prior to this visit due to chronic asthma; a week before the onset of illness, she had taken two dietary supplements to control her weight, one of which contained Garcinia Cambogia, which may be a contributing factor to two recent cases of hepatitis in the United States; in addition, both formulations contained citrus derivatives that interfere with cytochrome function. The authors hypothesize a causal relationship between the intake of the supplements and the fatal hepatitis, and propose a synergistic effect between the supplements and montelukast, which itself has been well-studied as a hepatotoxic drug. Although this claim is speculative, researchers believe that this warning may help raise awareness of the current uncontrolled increase in food additives. This case describes an asthmatic patient who developed severe obstructive symptoms and progressive heart failure after two consecutive exposures to montelukast. Due to a significantly elevated blood eosinophil count, diffuse infiltrates on chest X-ray, and signs of myocarditis, the patient was suspected of having Chaucer-Schwarz syndrome (CSS). The condition was confirmed by open-chest lung biopsy. Symptoms rapidly improved after administration of high-dose methylprednisolone and cyclophosphamide immunosuppressants. This case is noteworthy because its progression strongly suggests a direct causative role for montelukast in the development of CSS. However, its pathophysiological mechanism remains unclear.

[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 drug; Leukotriene antagonist
Montallukast is indicated for the prevention and chronic treatment of asthma in adults and children aged 12 months and older. /Included on US product label/
Montallukast is indicated for the relief of symptoms of seasonal allergic rhinitis in adults and children aged 2 years and older. /Included on US product label/
Montallukast is not indicated for the treatment of bronchospasm caused by acute asthma attacks (including status asthmaticus). /Not included on US product label/
Drug Warnings

Headache is the most common adverse reaction to montelukast, occurring in 18-19% of children aged 6 years and older, adolescents, and adults. Headache has been reported in at least 2% of asthmatic children aged 2-8 years receiving montelukast; and in at least 1% (and at a higher rate than in the placebo group) of asthmatic adults and adolescents aged 15 years and older receiving montelukast. In adults and adolescents aged 15 years and older with perennial allergic rhinitis treated with montelukast, sinus headache occurred in at least 1% of patients, with a higher incidence than in the placebo group. In clinical studies, approximately 1.8–1.9% of patients aged 15 years and older experienced dizziness or weakness/fatigue after treatment with this drug. Additionally, reports indicate that this drug may cause abnormal dreams, hallucinations, agitation (including aggressive behavior), paresthesia/hypopnea, somnolence, insomnia, irritability, or restlessness. Reports of seizures are very rare. In patients aged 15 years and older treated with montelukast, abdominal pain occurred in 2.9% of cases. In this age group, 2.1%, 1.5%, and 1.7% reported dyspepsia, infectious gastroenteritis, and toothache, respectively. In children aged 6–14 years treated with montelukast, at least 2% reported diarrhea or nausea. In children aged 2–5 years with asthma, at least 2% reported abdominal pain, diarrhea, and gastroenteritis, with an incidence higher than in the placebo group. In children aged 6–8 years with asthma, at least 2% reported gastroenteritis, with an incidence higher than in the placebo group. Post-marketing surveillance data showed that patients treated with montelukast may also experience adverse reactions such as nausea, vomiting, indigestion, pancreatitis (rare), and diarrhea. In clinical studies, patients treated with montelukast experienced one or more elevated liver function test results. In clinical studies, 2.1% and 1.6% of asthma patients aged 15 years and older treated with montelukast, respectively, experienced elevated serum ALT (SGPT) or AST (SGOT) concentrations. In clinical studies, at least 1% of adults and adolescents aged 15 years and older with perennial allergic rhinitis treated with montelukast experienced elevated ALT, with an incidence higher than in the placebo group. Changes in laboratory indicators returned to normal despite continued montelukast treatment, or were not directly caused by the drug. Elevated serum transaminase (TAM) levels have been reported in children aged 2–14 years taking montelukast, but the incidence was similar to that in children taking a placebo. Post-marketing experience shows that montelukast rarely causes hepatic eosinophilic infiltration. Post-marketing experience also shows that montelukast rarely causes hepatocellular injury, cholestatic hepatitis, or mixed hepatic injury. These patients mostly had confounding factors, such as concurrent use of other medications or alcohol consumption, or the presence of other diseases (e.g., other types of hepatitis). The incidence of rash in adults and adolescents aged 15 years and older taking montelukast was 1.6%. At least 2% of children aged 2–5 years taking the drug reported rashes, eczema, dermatitis, or urticaria. At least 2% of children aged 6–8 years with asthma treated with montelukast developed atopic dermatitis, varicella, and skin infections, with a higher incidence than in children receiving a placebo. Patients treated with montelukast have reported hypersensitivity reactions, including anaphylactic shock, angioedema, pruritus, urticaria, and, rarely, eosinophilic infiltration of the liver. For more complete data on drug warnings (out of 17) for montelukast, please visit the HSDB record page.
Pharmacodynamics
Montelukast is a leukotriene receptor antagonist with significant affinity and selectivity for cysteyl leukotriene receptor type 1, superior to many other important airway receptors such as prostaglandin receptors, cholinergic receptors, or β-adrenergic receptors. Therefore, even at doses as low as 5 mg, this drug can significantly block LTD4 leukotriene-mediated bronchoconstriction. Furthermore, a placebo-controlled crossover study (n=12) showed that montelukast inhibited early and late bronchoconstriction induced by antigen stimulation by 75% and 57%, respectively. Of particular note is the documented bronchodilation effect that can occur within 2 hours after oral administration of montelukast. This effect can also be additive with the bronchodilatory effect produced by the concurrent use of β-receptor agonists. However, clinical studies in adults aged 15 years and older have shown that daily administration of montelukast exceeding 10 mg does not provide additional clinical benefit. Furthermore, in clinical trials involving adults and children aged 6 to 14 years with asthma, studies have found that, during double-blind treatment, montelukast reduced the median peripheral blood eosinophil count by approximately 13% to 15% compared to placebo. Simultaneously, in patients aged 15 years and older with seasonal allergic rhinitis, montelukast also reduced the median peripheral blood eosinophil count by 13% compared to placebo.

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.)