A Comprehensive Pharmacological and Clinical Monograph on Zileuton

1.0 Introduction and Chemical Profile

1.1 Overview and Therapeutic Class

Zileuton is an orally active inhibitor of the 5-lipoxygenase (5-LOX) enzyme, positioning it within a distinct class of anti-inflammatory agents used for the prophylaxis and chronic treatment of asthma.[1] Its chemical structure and pharmacological mechanism differ significantly from other antiasthmatic drugs, particularly the more widely used leukotriene receptor antagonists (LTRAs) such as montelukast and zafirlukast.[1] While LTRAs block the action of leukotrienes at their receptor sites, zileuton acts upstream to prevent their synthesis altogether. This distinction is fundamental to understanding its efficacy and side effect profile.

The clinical history of zileuton is complex; it is an approved medication, but its immediate-release (IR) formulation was withdrawn from the United States market, while an extended-release (ER) version remains available.[1] This history reflects a balance between its therapeutic utility and challenges related to dosing convenience and safety monitoring.

1.2 Physicochemical Properties and Formulation

Zileuton is a synthetic organic compound with a well-defined chemical profile. Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea.[9] It is also known by several synonyms, including (±)-1-(1-Benzo[b]thien-2-ylethyl)-1-hydroxyurea and the development code A-64077.[1]

The drug is a racemic mixture, composed of a 50:50 ratio of its R(+) and S(-) enantiomers. Both enantiomers have been shown to be pharmacologically active as 5-lipoxygenase inhibitors in in vitro systems, meaning the entire mixture contributes to the therapeutic effect.[1]

Physically, zileuton is described as a practically odorless, white, crystalline powder. Its solubility characteristics are notable; it is soluble in organic solvents like methanol and ethanol but is practically insoluble in water, with a reported solubility of approximately 0.5 mg/mL.[11] The compound has a defined melting point range of 144.2°C to 145.2°C.[10] A summary of its key chemical and physical properties is provided in Table 1.

Property	Value	Source(s)
IUPAC Name	1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea	9
DrugBank ID	DB00744	1
CAS Number	111406-87-2	9
Molecular Formula	C11​H12​N2​O2​S	1
Molecular Weight	236.29 g/mol	1
Appearance	White, crystalline powder	11
Solubility in Water	0.5 mg/mL (practically insoluble)	11
Melting Point	144.2–145.2 °C	10
Stereochemistry	Racemic mixture of active R(+) and S(-) enantiomers	1

Table 1: Chemical and Physical Properties of Zileuton. This table consolidates key identifiers and physicochemical characteristics of zileuton.

2.0 Pharmacodynamics: Mechanism of 5-Lipoxygenase Inhibition

2.1 The Leukotriene Pathway in Asthma Pathophysiology

Asthma is fundamentally a chronic inflammatory disorder of the airways, where various endogenous mediators orchestrate a complex pathological response. Among the most potent of these mediators are the leukotrienes.[1] These lipid-derived signaling molecules are synthesized from arachidonic acid via the 5-lipoxygenase (5-LOX) pathway.[1] The leukotriene family includes leukotriene B4 (LTB4), a powerful chemoattractant for neutrophils and eosinophils, and the cysteinyl leukotrienes (CysLTs): LTC4, LTD4, and LTE4. The CysLTs were historically known as the slow-releasing substances of anaphylaxis.[1]

Collectively, these leukotrienes induce a cascade of biological effects that define the asthmatic phenotype. They promote the migration and aggregation of inflammatory cells like neutrophils and eosinophils, enhance leukocyte adhesion to the vascular endothelium, increase capillary permeability leading to airway edema, stimulate mucus secretion, and cause potent contraction of bronchial smooth muscle.[1] This combination of effects results in the characteristic airway inflammation, edema, mucus plugging, and bronchoconstriction seen in patients with asthma.[4]

2.2 Molecular Target and Mechanism of Action

Zileuton exerts its therapeutic effect by directly targeting and inhibiting the enzyme arachidonate 5-lipoxygenase (ALOX5).[1] This enzyme is the critical catalyst in the first step of the leukotriene biosynthetic pathway, converting arachidonic acid into an unstable intermediate, leukotriene A4 (LTA4).[1] By inhibiting 5-LOX, zileuton effectively halts the production of all subsequent leukotrienes, including both LTB4 and the cysteinyl leukotrienes (LTC4, LTD4, and LTE4).[1]

This upstream point of intervention is the key mechanistic distinction between zileuton and the leukotriene receptor antagonists (LTRAs) like montelukast. While LTRAs selectively block the CysLT1 receptor, leaving the LTB4 pathway and other potential CysLT receptors unaffected, zileuton provides a comprehensive blockade of the entire leukotriene cascade.[5] As a racemic mixture, both the R(+) and S(-) enantiomers of zileuton contribute to this inhibitory activity.[1]

2.3 Pharmacodynamic Effects

The pharmacodynamic activity of zileuton has been demonstrated in both preclinical models and human studies. In animal models, zileuton has been shown to inhibit arachidonic acid-induced ear edema in mice and to block leukotriene-dependent bronchospasm in guinea pigs.[4] In human clinical settings, pretreatment with zileuton effectively attenuated the bronchoconstriction caused by cold air challenge, a standard model for assessing airway hyperreactivity in asthmatic patients.[1] These effects confirm that by interrupting leukotriene synthesis, zileuton can mitigate key pathophysiological processes in asthma.

3.0 Clinical Pharmacokinetics (ADME)

3.1 Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic profile of zileuton is characterized by rapid absorption and extensive metabolism.

• Absorption: Following oral administration, zileuton is rapidly and almost completely absorbed. The immediate-release (IR) formulation reaches a mean time to peak plasma concentration (Tmax) of approximately 1.7 hours.[1] The bioavailability of the extended-release (ER) formulation is significantly influenced by food, which increases the extent of absorption and is therefore recommended to be taken with meals.[17]
• Distribution: Zileuton has an apparent volume of distribution of approximately 1.2 L/kg. It is highly bound (93%) to plasma proteins, primarily albumin.[1]
• Metabolism: Zileuton is extensively metabolized by the liver. This biotransformation is carried out by the cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C9, and CYP3A4.[1] This metabolic pathway is the primary source of zileuton's clinically significant drug-drug interactions. The main metabolic products are inactive glucuronide conjugates and an N-dehydroxylated metabolite.[1]
• Excretion: Elimination is predominantly through hepatic metabolism. The IR formulation has a mean terminal half-life of approximately 2.5 hours.[1] Following a radiolabeled dose, about 95% of the radioactivity is recovered in the urine as metabolites, with less than 0.5% excreted as unchanged drug.[1]

3.2 Comparative Analysis: Immediate-Release vs. Extended-Release Formulations

The development of an extended-release formulation (Zyflo CR) was a direct response to the market challenges posed by the immediate-release version (Zyflo), which required a four-times-daily dosing schedule.[5] The goal of the ER formulation was to improve patient compliance and convenience by allowing for twice-daily administration.[21]

Pharmacokinetic studies comparing the two formulations revealed key differences. While a direct head-to-head study was not performed, comparisons of each formulation against the IR version in separate studies allow for a cross-study analysis.[22] At steady state, when taken with food as recommended, the ER formulation (1200 mg twice daily) produces a lower peak plasma concentration (Cmax) that is approximately 35% lower than that of the IR formulation (600 mg four times daily). However, the minimum concentration (Cmin) and the total drug exposure over 24 hours (AUC) are similar for both formulations. This indicates that the ER version successfully provides sustained therapeutic drug levels throughout the dosing interval with less peak-trough fluctuation, justifying the more convenient twice-daily regimen.[17] These pharmacokinetic properties are summarized in Table 2.

Parameter	Zileuton IR (600 mg QID)	Zileuton ER (1200 mg BID)	Note
Dosing	Four times daily	Twice daily, with food	5
Tmax​ (single dose, fasted)	~1.7 hours	~2.1 hours	11
Cmax​ (steady state, fed)	Higher peak concentration	~35% lower than IR	17
AUC (steady state, fed)	Similar to ER	Similar to IR	17
Cmin​ (steady state, fed)	Lower than ER	Higher than IR	17

Table 2: Comparative Pharmacokinetic Parameters of Zileuton IR and ER Formulations. Data compiled from multiple studies show the ER formulation provides similar overall exposure with lower peak concentrations compared to the IR formulation.

4.0 Clinical Efficacy and Therapeutic Use

4.1 Management of Chronic Asthma

Zileuton is FDA-approved for the prophylaxis and chronic treatment of asthma in adults and children aged 12 years and older.[2] It is important to note that it is not indicated for the treatment of acute asthma attacks, as its mechanism of action does not provide immediate bronchodilation.[2]

Pivotal clinical trials established its efficacy. In placebo-controlled studies involving patients with mild to moderate asthma, treatment with zileuton 600 mg four times daily resulted in statistically significant improvements in lung function, as measured by the forced expiratory volume in one second (FEV1). These trials reported FEV1 increases ranging from 13.4% to 15.7% compared to placebo.[6] Furthermore, treatment was associated with a reduction in asthma exacerbations requiring the use of oral corticosteroids.[11]

4.2 Comparative Efficacy in the Asthma Treatment Landscape

Zileuton's place in asthma therapy is best understood in comparison to other available treatments.

• Versus Montelukast: In a randomized, double-blind study of patients with acute asthma, zileuton was found to be superior to the LTRA montelukast in improving lung function, as measured by peak expiratory flow rate (PEFR). While both drugs significantly reduced the need for rescue medications compared to placebo, only zileuton demonstrated a statistically significant improvement in PEFR.[24] This suggests a potential advantage for upstream 5-LOX inhibition over CysLT1 receptor antagonism in certain settings.
• Versus Inhaled Corticosteroids (ICS): Inhaled corticosteroids are considered the gold standard for the long-term control of persistent asthma. Meta-analyses and clinical guidelines generally position leukotriene modifiers, including zileuton, as less effective than ICS for first-line maintenance therapy.[26] Consequently, zileuton is typically considered an alternative therapy for patients who cannot or will not use ICS, or as an add-on therapy for patients whose asthma is not adequately controlled on ICS alone.

Study	Population	Intervention	Key Outcomes	Source(s)
Placebo-Controlled Trial	Mild to moderate asthma	Zileuton 600 mg QID vs. Placebo	15.7% improvement in FEV1 vs. 7.7% for placebo; fewer exacerbations.	6
Placebo-Controlled Trial	Mild to moderate asthma	Zileuton 600 mg QID vs. Placebo	13.4% improvement in FEV1 vs. placebo.	11
Comparative Trial	Acute asthma	Zileuton vs. Montelukast vs. Placebo	Zileuton significantly improved PEFR vs. placebo (p=0.007); montelukast did not. Both reduced need for rescue medication.	24

Table 3: Summary of Key Clinical Trials on Zileuton Efficacy in Asthma.

4.3 Investigational and Off-Label Applications

The anti-inflammatory properties of zileuton have prompted investigation into its use for other conditions characterized by leukotriene-mediated pathology.

• Aspirin-Exacerbated Respiratory Disease (AERD): Zileuton is used off-label for AERD, a condition characterized by asthma, chronic rhinosinusitis with nasal polyps, and sensitivity to aspirin and other NSAIDs. Research suggests that by inhibiting the overproduction of leukotrienes central to this disease, zileuton may reduce the need for sinus surgeries in these patients.[18]
• Chronic Obstructive Pulmonary Disease (COPD): Given the inflammatory component of COPD, zileuton has been studied for this condition, with research supporting its potential efficacy.[18]
• Other Conditions: Zileuton has also been investigated for use in various dermatological conditions, such as acne and atopic dermatitis, and even in preclinical models of chronic myeloid leukemia.[18]

5.0 Safety, Tolerability, and Risk Management

5.1 Hepatotoxicity: The Primary Safety Concern

The most significant safety issue associated with zileuton therapy is the risk of hepatotoxicity, which necessitates careful patient selection and rigorous monitoring.

• Clinical Pattern: Zileuton can cause elevations in serum aminotransferases, particularly alanine aminotransferase (ALT), which is the most sensitive indicator of liver injury with this drug.[15] These elevations are typically asymptomatic and occur within the first three months of treatment.[28] In clinical trials, ALT elevations of three times the upper limit of normal (ULN) or greater occurred in 2-5% of patients receiving zileuton, compared to approximately 1% of placebo recipients.[2] While these elevations are usually reversible upon discontinuation of the drug, rare cases of more severe, symptomatic hepatitis with jaundice have been reported.[15]
• Risk Factors: The risk of hepatotoxicity appears to be higher in females over the age of 65.[30] Zileuton is contraindicated in patients with active liver disease and should be used with caution in those with a history of liver disease or who consume substantial amounts of alcohol.[29]
• FDA-Mandated Hepatic Monitoring: Due to the risk of liver injury, the FDA requires a strict monitoring schedule. Liver function tests must be performed at baseline before starting therapy, then monthly for the first three months, every two to three months for the remainder of the first year, and periodically thereafter for patients on long-term therapy.[2]

5.2 Proposed Biochemical Mechanisms of Hepatotoxicity

The hepatotoxicity associated with zileuton is not considered an off-target effect but rather an outcome of its metabolic processing. The pattern of liver enzyme elevation is predominantly hepatocellular, suggesting direct injury to liver cells.[18]

The leading hypothesis for the mechanism of this injury involves the bioactivation of zileuton's benzothiophene moiety. This chemical structure is similar to that of tienilic acid, another drug known to cause liver injury through a similar mechanism. It is proposed that zileuton is first metabolized by cytochrome P450 enzymes to a reactive S-oxide intermediate. This electrophilic metabolite can then form covalent adducts with cellular macromolecules or deplete glutathione stores, leading to cellular damage. Subsequent research in animal models has supported this theory, linking zileuton exposure to nitrosative stress, mitochondrial dysfunction, and altered fatty acid oxidation in susceptible individuals, ultimately resulting in hepatocellular necrosis.[33] This detailed biochemical pathway provides a strong rationale for why the liver is the primary target of toxicity and underscores the critical importance of the mandated monitoring protocol.

5.3 Neuropsychiatric Adverse Events

The FDA label for zileuton includes a warning for potential neuropsychiatric events, such as sleep disorders and behavioral changes.[2] This is considered a class effect for leukotriene-modifying agents. However, post-marketing surveillance data suggest that such events are reported far less frequently with zileuton compared to the LTRA montelukast.[36] The precise mechanism for these effects is unknown, but the difference in frequency may be related to the distinct mechanisms of action—zileuton's upstream synthesis inhibition versus montelukast's downstream receptor antagonism.[36] This distinction is an important consideration in the clinical risk-benefit assessment for patients with a history of neuropsychiatric conditions.

5.4 Other Common and Serious Adverse Reactions

The most common adverse reactions reported in clinical trials (≥5%) were sinusitis, nausea, and pharyngolaryngeal (throat) pain.[17] Other frequently reported side effects include headache, myalgia (muscle pain), and dyspepsia (indigestion).[3]

6.0 Clinically Significant Drug-Drug Interactions

6.1 Interactions with Theophylline, Warfarin, and Propranolol

Zileuton's metabolism via CYP1A2, CYP2C9, and CYP3A4 makes it a perpetrator of several clinically important drug-drug interactions, primarily through its weak inhibitory effect on CYP1A2 and CYP2C9.[1]

• Theophylline: Co-administration of zileuton can approximately double the serum concentration of theophylline, a CYP1A2 substrate with a narrow therapeutic index. This can lead to theophylline toxicity. It is recommended that the theophylline dose be reduced by approximately 50% when starting zileuton, with close monitoring of serum theophylline levels.[2]
• Warfarin: Zileuton can increase the levels of R-warfarin (metabolized by CYP1A2 and CYP3A4), leading to a clinically significant increase in prothrombin time (PT) and the risk of bleeding. The S-warfarin enantiomer (metabolized by CYP2C9) is less affected. Close monitoring of PT or INR is essential, and the warfarin dose should be adjusted accordingly.[12]
• Propranolol: Zileuton can double the area under the curve (AUC) for propranolol, a substrate of CYP2C9 and CYP1A2, leading to increased beta-blocker activity (e.g., bradycardia). Patients should be monitored closely, and the propranolol dose may need to be reduced.[12]

6.2 Broader Implications for CYP450-Metabolized Drugs

The well-documented interactions with theophylline, warfarin, and propranolol serve as important models for predicting other potential interactions. Clinicians should exercise caution when co-administering zileuton with any drug that is a sensitive substrate of CYP1A2 or CYP2C9, particularly those with a narrow therapeutic window. A summary of these key interactions is provided in Table 4.

Interacting Drug	Affected CYP Enzyme	Clinical Consequence	Management Recommendation	Source(s)
Theophylline	CYP1A2	Increased theophylline levels, risk of toxicity	Reduce theophylline dose by ~50%; monitor serum levels	2
Warfarin	CYP1A2, CYP2C9	Increased prothrombin time (PT), risk of bleeding	Monitor PT/INR closely; adjust warfarin dose	12
Propranolol	CYP1A2, CYP2C9	Increased beta-blocker activity (e.g., bradycardia)	Monitor patient; reduce propranolol dose as needed	12
Caffeine	CYP1A2	Potentially reduced clearance of caffeine	Monitor for effects of increased caffeine levels	5

Table 4: Summary of Significant Drug-Drug Interactions with Zileuton.

7.0 Special Topics in Zileuton Therapy

7.1 Pharmacogenomics: The Role of ALOX5 Variants in Treatment Response

A significant factor contributing to the inter-individual variability in response to zileuton lies in the pharmacogenomics of its target enzyme, 5-lipoxygenase, which is encoded by the ALOX5 gene.[41] The promoter region of the

ALOX5 gene contains a variable number of tandem repeats (VNTR) of the sequence GGGCGG. The most common allele, considered the wild-type, contains five repeats. Variant alleles with fewer or more repeats exist and have been shown to affect the gene's expression and, consequently, the response to 5-LOX inhibitors.[41]

Clinical studies have demonstrated a clear association between these ALOX5 promoter polymorphisms and patient response to zileuton. Patients who are homozygous for the common five-repeat allele tend to show a more robust improvement in FEV1 when treated with zileuton. In contrast, patients carrying variant alleles often show a diminished response.[43] A similar association has been found for specific single nucleotide polymorphisms (SNPs) within the gene, such as rs2115819.[42] This genetic variability provides a molecular basis for why some patients benefit more from zileuton than others. These findings suggest a potential future role for pharmacogenomic testing to stratify patients and personalize asthma therapy, identifying individuals who are most likely to respond favorably to 5-LOX inhibition.

7.2 Market History: The Withdrawal of the Immediate-Release Formulation

On February 12, 2008, the immediate-release formulation of zileuton (Zyflo) was withdrawn from the U.S. market by its then-marketer, Critical Therapeutics.[8] It is crucial to understand that this was a commercial decision and not a mandatory recall initiated by the FDA for safety reasons.

An examination of SEC filings from that period reveals the underlying business rationale. The IR formulation struggled to gain significant market acceptance due to its inconvenient four-times-daily dosing regimen.[20] In a competitive landscape where other oral asthma medications offered once- or twice-daily dosing, the compliance burden of ZYFLO was a major disadvantage. Furthermore, physician perceptions about the necessity of frequent liver function monitoring were a barrier to prescription, with some viewing the requirement as inconvenient or indicative of a significant safety risk compared to alternatives.[20] The development and approval of the extended-release Zyflo CR, with its twice-daily dosing, was a direct strategic effort to address these commercial challenges and improve the drug's market position.[22]

8.0 Conclusion and Expert Recommendations

8.1 Synthesis of Zileuton's Therapeutic Profile

Zileuton is a mechanistically distinct oral anti-inflammatory agent for the management of chronic asthma. Its unique action as a 5-lipoxygenase inhibitor allows it to block the entire leukotriene synthesis pathway, offering a broader anti-inflammatory effect compared to leukotriene receptor antagonists. Clinical evidence supports its efficacy, demonstrating modest but statistically significant improvements in lung function and a reduction in asthma exacerbations.

However, its therapeutic utility is significantly tempered by two key factors. The first is the risk of hepatotoxicity, a dose-related effect linked to the metabolic bioactivation of the drug's benzothiophene core. This risk necessitates a rigorous and non-negotiable schedule of liver function monitoring, which can be a barrier for both patients and prescribers. The second factor is its potential for clinically significant drug-drug interactions through the inhibition of CYP1A2 and CYP2C9, requiring careful management of concomitant medications. These considerations, along with the availability of other effective and more conveniently administered asthma therapies, have positioned zileuton as an alternative or add-on therapy rather than a first-line agent.

8.2 Recommendations for Clinical Practice and Patient Selection

Based on its comprehensive profile, the use of zileuton in clinical practice should be carefully considered.

• Patient Selection: Zileuton is a reasonable therapeutic option for adults and adolescents (≥12 years) with mild-to-moderate persistent asthma who are either intolerant of, or inadequately controlled by, standard therapies such as inhaled corticosteroids. It may be particularly beneficial for patients with specific asthma phenotypes where leukotrienes play a dominant role, such as aspirin-exacerbated respiratory disease (AERD). In the future, pharmacogenomic testing for ALOX5 variants could further refine patient selection to identify those most likely to respond.
• Safety and Monitoring: Absolute adherence to the FDA-mandated schedule for liver function monitoring is paramount to ensure patient safety. Zileuton is contraindicated in patients with active liver disease. A thorough patient history, including alcohol consumption, must be obtained before initiating therapy.
• Drug Interactions: A comprehensive review of a patient's current medications is essential before prescribing zileuton. For patients on narrow therapeutic index drugs metabolized by CYP1A2 or CYP2C9, such as theophylline and warfarin, dose adjustments and intensive monitoring are required.
• Patient Counseling: Patients must be educated on the importance of adherence to the prescribed dosing schedule (twice daily with meals for the ER formulation) and the critical need for regular blood tests to monitor liver function. They should also be counseled on the signs and symptoms of liver injury and instructed to report them immediately.

Works cited

1. Zileuton: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed June 19, 2025, https://go.drugbank.com/drugs/DB00744
2. ZYFLO CR (zileuton) extended-release tablets - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022052s014lbl.pdf
3. Zileuton: MedlinePlus Drug Information, accessed June 19, 2025, https://medlineplus.gov/druginfo/meds/a697013.html
4. zileuton tablet Cornerstone Therapeutics Inc. Zyflo - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020471s014,022052s005lbl.pdf
5. Zileuton - Wikipedia, accessed June 19, 2025, https://en.wikipedia.org/wiki/Zileuton
6. Antileukotrienes and asthma: Alternative or adjunct to inhaled steroids? - Cleveland Clinic Journal of Medicine, accessed June 19, 2025, https://www.ccjm.org/content/ccjom/65/10/519.full.pdf
7. Zileuton (oral route) - Mayo Clinic, accessed June 19, 2025, https://www.mayoclinic.org/drugs-supplements/zileuton-oral-route/description/drg-20066760
8. Zileuton Advanced Patient Information - Drugs.com, accessed June 19, 2025, https://www.drugs.com/cons/zileuton.html
9. zileuton | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed June 19, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5297
10. Zileuton | C11H12N2O2S | CID 60490 - PubChem, accessed June 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Zileuton
11. ZYFLO® (zileuton tablets) DESCRIPTION Zileuton is an orally active inhibitor of 5-lipoxygenase, the enzyme that catalyzes the f - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020471s017lbl.pdf
12. Page 1 of 14 Part number 42000R00-Rev. March 2005 ZYFLO® (zileuton tablets) Tear at perforation to dispense patient information - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020471s011lbl.pdf
13. Zileuton MATERIAL SAFETY DATA SHEET - Amazon S3, accessed June 19, 2025, https://s3-us-west-2.amazonaws.com/drugbank/msds/DB00744.pdf?1265922743
14. ZILEUTON - GSRS, accessed June 19, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/V1L22WVE2S
15. Zileuton - LiverTox - NCBI Bookshelf, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548397/
16. What is the mechanism of Zileuton? - Patsnap Synapse, accessed June 19, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-zileuton
17. Label: ZILEUTON tablet, extended release - DailyMed, accessed June 19, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fd382540-b390-4e86-a94a-988ea89c93a8
18. Zileuton - StatPearls - NCBI Bookshelf, accessed June 19, 2025, https://www.ncbi.nlm.nih.gov/books/NBK448202/
19. What is Zileuton used for? - Patsnap Synapse, accessed June 19, 2025, https://synapse.patsnap.com/article/what-is-zileuton-used-for
20. exv99w3 - SEC.gov, accessed June 19, 2025, https://www.sec.gov/Archives/edgar/data/1145404/000095013508006951/b72760ctexv99w3.htm
21. Zileuton Monograph for Professionals - Drugs.com, accessed June 19, 2025, https://www.drugs.com/monograph/zileuton.html
22. Zyflo XR (zileuton) Extended Release Tablets 600mg - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022052s000_MedR_P1.pdf
23. Zyflo CR Advanced Patient Information - Drugs.com, accessed June 19, 2025, https://www.drugs.com/cons/zyflo-cr.html
24. Comparison of oral montelukast with oral zileuton in acute asthma: A ..., accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4857564/
25. Comparison of oral montelukast with oral zileuton in acute asthma: A randomized, double-blind, placebo-controlled study - ResearchGate, accessed June 19, 2025, https://www.researchgate.net/publication/301575590_Comparison_of_oral_montelukast_with_oral_zileuton_in_acute_asthma_A_randomized_double-blind_placebo-controlled_study
26. Asthma: Resource use and costs for inhaled corticosteroid vs leukotriene modifier treatment—a meta-analysis, accessed June 19, 2025, https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/5205JFP_OriginalResearch.pdf
27. Leukotriene Inhibitors in the Treatment of Allergy and Asthma - AAFP, accessed June 19, 2025, https://www.aafp.org/pubs/afp/issues/2007/0101/p65.html
28. Zileuton: Package Insert / Prescribing Information - Drugs.com, accessed June 19, 2025, https://www.drugs.com/pro/zileuton.html
29. Zileuton Disease Interactions - Drugs.com, accessed June 19, 2025, https://www.drugs.com/disease-interactions/zileuton.html?professional=1
30. Clinical Pattern of Zileuton-Associated Liver Injury | Request PDF - ResearchGate, accessed June 19, 2025, https://www.researchgate.net/publication/276956730_Clinical_Pattern_of_Zileuton-Associated_Liver_Injury
31. Zileuton | Drug Lookup | Pediatric Care Online - AAP Publications, accessed June 19, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5179/Zileuton
32. ZYFLO CR (zileuton) extended-release tablets - accessdata.fda.gov, accessed June 19, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022052s005lbl.pdf
33. In Vitro Metabolism of 2-Acetylbenzothiophene: Relevance to ..., accessed June 19, 2025, https://pubs.acs.org/doi/pdf/10.1021/tx0341409
34. Clinical pattern of zileuton-associated liver injury: Results of a 12-month study in patients with chronic asthma | Request PDF - ResearchGate, accessed June 19, 2025, https://www.researchgate.net/publication/6117318_Clinical_pattern_of_zileuton-associated_liver_injury_Results_of_a_12-month_study_in_patients_with_chronic_asthma
35. Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice | Toxicological Sciences | Oxford Academic, accessed June 19, 2025, https://academic.oup.com/toxsci/article-abstract/175/2/220/5805400
36. Anti-leukotriene drugs - World Allergy Organization, accessed June 19, 2025, https://www.worldallergy.org/component/content/article/anti-leukotriene-drugs?catid=17&Itemid=101
37. Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug−gene Interaction Network - Frontiers, accessed June 19, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.764279/full
38. Zileuton Uses, Side Effects & Warnings - Drugs.com, accessed June 19, 2025, https://www.drugs.com/mtm/zileuton.html
39. table 6 - AAFP, accessed June 19, 2025, https://www.aafp.org/pubs/afp/issues/1998/0701/p89/jcr:content/root/aafp-article-primary-content-container/aafp_article_main_par/aafp_tables_content4.print.html
40. Zileuton (Zyflo) Tablets: Uses & Side Effects - Cleveland Clinic, accessed June 19, 2025, https://my.clevelandclinic.org/health/drugs/20079-zileuton-tablets
41. Leukotriene modifiers pathway, Pharmacodynamics - PharmGKB, accessed June 19, 2025, https://www.pharmgkb.org/pathway/PA165947317
42. PhenoModifier-Gene Detail, accessed June 19, 2025, https://www.biosino.org/PhenoModifier/gene/item?id=51
43. 5-lipoxygenase Pharmacogenetics in Asthma: Overlap with ..., accessed June 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2731688/
44. CRITICAL THERAPEUTICS, INC. - SEC.gov, accessed June 19, 2025, https://www.sec.gov/Archives/edgar/data/1145404/000095013504002764/b49788a3sv1za.htm
45. deliveringon our mission - SEC.gov, accessed June 19, 2025, https://www.sec.gov/Archives/edgar/vprr/0901/09011070.pdf