Zileuton

0.9

2.05

Practically insoluble (0.5 mg/ml)

5.39e-02 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Asthmatic Agents; Leukotriene Antagonists; Lipoxygenase Inhibitors

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

144.2-145.2 °C

144.2 - 145.2 °C

156.4 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID9023752]

143.57 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P264+P265, P270, P280, P301+P317, P305+P351+P338, P330, P337+P317, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 43 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In premarketing studies, zileuton therapy was found to be associated with mild-to-moderate serum aminotransferase elevations. In large prospective studies, ALT elevations above 3 times the upper limit of the normal range occurred in 1.9% of patients treated with zileuton for at least one year, compared to 0.2% of placebo recipients. These elevations were usually transient, asymptomatic and rapidly reversible. However, some patients with ALT elevations reported symptoms suggestive of hepatic injury (fatigue, nausea, abdominal pain) and individual cases of clinically apparent, frank liver injury with jaundice were seen. The typical onset of liver enzyme elevations was within 4 to 8 weeks of starting zileuton, but cases arising after 6 months were also reported. In cases with jaundice, the pattern of serum enzyme elevations was hepatocellular. Immunoallergic and autoimmune features were not prominent. Recovery was rapid, usually within 1 to 2 months. Overall, however, only isolated cases of zileuton related liver injury with jaundice have been reported, and clinically apparent hepatotoxicity from it must be very rare. Results of rechallenge have not been reported. Because of the frequency of serum enzyme elevations during zileuton therapy, monitoring of serum aminotransferase levels is recommended and its use is considered contraindicated in patients with active liver disease. The lack of published reports of zileuton hepatotoxicity may be due to active monitoring for liver test abnormalities and prompt discontinuation if they persist or continue to rise. In addition, zileuton has not been as widely used clinically as montelukast or zafirlukast.

Zileuton is an asthma drug that differs chemically and pharmacologically from other antiasthmatic agents. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Current data indicates that asthma is a chronic inflammatory disorder of the airways involving the production and activity of several endogenous inflammatory mediators, including leukotrienes. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, are derived from the initial unstable product of arachidonic acid metabolism, leukotriene A4 (LTA4), and can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. In humans, pretreatment with zileuton attenuated bronchoconstriction caused by cold air challenge in patients with asthma.

Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Zileuton relieves such symptoms through its selective inhibition of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid. Specifically, it inhibits leukotriene LTB4, LTC4, LTD4, and LTE4 formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in <i>in vitro</i> systems. Due to the role of leukotrienes in the pathogenesis of asthma, modulation of leukotriene formation by interruption of 5-lipoxygenase activity may reduce airway symptoms, decrease bronchial smooth muscle tone, and improve asthma control.

Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4.