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药品详细

Zileuton(齐留通)

化学结构式图
中文名
齐留通
英文名
Zileuton
分子式
C11H12N2O2S
化学名
1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea
分子量
Average: 236.29
Monoisotopic: 236.061948328
CAS号
111406-87-2
ATC分类
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

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 in vitro systems.

生产厂家
  • Cornerstone therapeutics inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Berger W, De Chandt MT, Cairns CB: Zileuton: clinical implications of 5-Lipoxygenase inhibition in severe airway disease. Int J Clin Pract. 2007 Apr;61(4):663-76. Pubmed
  2. Wenzel SE, Kamada AK: Zileuton: the first 5-lipoxygenase inhibitor for the treatment of asthma. Ann Pharmacother. 1996 Jul-Aug;30(7-8):858-64. Pubmed
  3. Malo PE, Bell RL, Shaughnessy TK, Summers JB, Brooks DW, Carter GW: The 5-lipoxygenase inhibitory activity of zileuton in in vitro and in vivo models of antigen-induced airway anaphylaxis. Pulm Pharmacol. 1994 Apr;7(2):73-9. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Benzothiophenes
Substructures
  • Hydroxy Compounds
  • Benzene and Derivatives
  • Ureas and Derivatives
  • Carbamates and Derivatives
  • Benzothiophenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Thiophenes
  • Hydroxylamines and Derivatives
适应症
药理
Indication For the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older.
Pharmacodynamics 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.
Mechanism of action 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 in vitro 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.
Absorption Rapidly and almost completely absorbed. The absolute bioavailability is unknown.
Volume of distribution
  • 1.2 L/kg
Protein binding 93% bound to plasma proteins, primarily to albumin.
Metabolism
Hepatic. Zileuton and its N-dehydroxylated metabolite are oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Zileuton
Hydroxyzileuton Details
Zileuton
Zileuton sulfoxide Details
Zileuton
Dehydroxyzyleuton Details
Zileuton
Zileuton O-glucuronide Details
Zileuton
2-(4'-Diethylaminophenyl)benzothiazole Details
Zileuton
sulfoxide Details
Route of elimination Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose.
Half life 2.5 hours
Clearance
  • Apparent oral cl=7 mL/min/kg
Toxicity The oral minimum lethal doses in mice and rats were 500-4000 and 300-1000 mg/kg in various preparations, respectively (providing greater than 3 and 9 times the systemic exposure [AUC] achieved at the maximum recommended human daily oral dose, respectively).
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 144.2-145.2 °C Not Available
water solubility Practically insoluble (0.5 mg/ml) Not Available
logP 0.9 Not Available
Predicted Properties
Property Value Source
water solubility 5.39e-02 g/l ALOGPS
logP 2.01 ALOGPS
logP 2.01 ChemAxon
logS -3.6 ALOGPS
pKa (strongest acidic) 8.84 ChemAxon
pKa (strongest basic) -5.5 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 66.56 ChemAxon
rotatable bond count 2 ChemAxon
refractivity 61.96 ChemAxon
polarizability 24.14 ChemAxon
药物相互作用
Drug Interaction
Aminophylline Zileuton increases the effect and toxicity of theophylline
Bendamustine CYP1A2 metabolism may result in increased levels of active metabolites, decreases levels of bendamustine.
Dihydroergotamine Possible ergotism and severe ischemia with this combination
Eltrombopag Affects hepatic enzyme CYP1A2 metabolism and may increase the level of eltrombopag.
Ergotamine Possible ergotism and severe ischemia with this combination
Oxtriphylline Zileuton increases the effect and toxicity of theophylline
Pimozide Increased risk of cardiotoxicity and arrhythmias
Ramelteon Zileuton increases levels/toxicity of ramelteon
Theophylline Zileuton may increase the therapeutic and adverse effects of theophylline by increasing its serum concentration. Monitor for changes in the therapeutic and adverse effects of theophylline if zileuton is initiated, discontinued or dose changed. Dose alterations should be considered.
食物相互作用
Not Available

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