Zileuton
Encyclopedia
Zileuton is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4) formation. Zileuton is used for the maintenance treatment of asthma
. Zileuton was introduced in 1996 by Abbott Laboratories
and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names ZYFLO and ZYFLO CR. The original immediate-release formulation of zileuton, known as ZYFLO, is taken four times per day. The extended-release formulation, ZYFLO CR, is taken twice daily.
Although the extended release formulation of zileuton is still available (Zyflo CR), the immediate release tablet was withdrawn from the U.S. market on February 12, 2008.
in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma.
The recommended dose of ZYFLO is one 600 mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose of ZYFLO CR is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a daily dose of 2400 mg. Do not split ZYFLO CR tablets in half.
Related compounds include montelukast
(Singulair) and zafirlukast
(Accolate). These two compounds are leukotriene receptor antagonists which block the action of specific leukotrienes, while zileuton inhibits leukotriene formation.
Research on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukemia (CML).
Neuropsychiatric events, including sleep disorders and behavioral changes, may occur with ZYFLO and ZYFLO CR. Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using ZYFLO or ZYFLO CR.
Zileuton is a weak inhibitor of CYP1A2
and thus has three clinically important drug interactions, which include increasing warfarin
, theophylline
, and propranolol levels. It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%. Because of theophylline's relation to caffeine
(both being a methylxanthine, and theophylline being a metabolite of caffeine), caffeine's metabolism and clearance may also be reduced, but there are no drug interaction studies between zileuton and caffeine. The R-isomer of warfarin metabolism and clearance is mainly affected by zileuton, while the S-isomer is not (because of metabolism via different enzymes). This can lead to an increase in prothrombin time.
. The chemical name of zileuton is (±)-1-(1-Benzo[b]thien-2-ylethyl)-l-hydroxyurea.
The molecular formula of zileuton is C11H12N2O2S with a molecular weight of 236.29. The formulation from the manufacturer is a racemic mixture of R(+) and S(-) enantiomers.
concentration of 1.7 hours and an average half-life elimination of 2.5 hours. Blood plasma
concentrations are proportional to dose, whereas the absolute bioavailability
is unknown.
The apparent volume of distribution
of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin
, with minor binding to alpha-1-acid glycoprotein.
Elimination of zileuton is primarily through metabolites in the urine (~95%) with the feces accounting for the next largest amount (~2%). The drug is metabolized by the cytochrome P450 enzymes: CYP1A2, 2C9, and 3A4.
(6.5%), nausea
(5%), and pharyngolaryngeal pain (5%) vs. placebo, 4%, 1.5%, and 4% respectively.
, propranolol, and warfarin
. It is advised that the doses of each medication be monitored and/or reduced accordingly.
is recommended due to increase risk of CNS depression as well as an increase risk in liver toxicity. In addition, the herbal supplement St. John's wort may decrease the serum levels of zileuton.
The oral minimum lethal doses in mice and rats were 500-4000 and 300–1000 mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000 mg/kg (providing in excess of 12 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose) no deaths occurred by nephritis was reported.
; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with ZYFLO CR.
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
. Zileuton was introduced in 1996 by Abbott Laboratories
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
and is now marketed in two formulations by Cornerstone Therapeutics Inc. under the brand names ZYFLO and ZYFLO CR. The original immediate-release formulation of zileuton, known as ZYFLO, is taken four times per day. The extended-release formulation, ZYFLO CR, is taken twice daily.
Although the extended release formulation of zileuton is still available (Zyflo CR), the immediate release tablet was withdrawn from the U.S. market on February 12, 2008.
Indications and dosing
Zileuton is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is not indicated for use in the reversal of bronchospasmBronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma.
The recommended dose of ZYFLO is one 600 mg tablet, four times per day. The tablets may be split in half to make them easier to swallow. The recommended dose of ZYFLO CR is two 600 mg extended-release tablets twice daily, within one hour after morning and evening meals, for a daily dose of 2400 mg. Do not split ZYFLO CR tablets in half.
Related compounds include montelukast
Montelukast
Montelukast is a leukotriene receptor antagonist used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally...
(Singulair) and zafirlukast
Zafirlukast
Zafirlukast is an oral leukotriene receptor antagonist for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. It is available as a tablet and is usually dosed twice daily. Another leukotriene receptor antagonist is montelukast...
(Accolate). These two compounds are leukotriene receptor antagonists which block the action of specific leukotrienes, while zileuton inhibits leukotriene formation.
Research on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukemia (CML).
Contraindications and warnings
The most serious side effect of ZYFLO and ZYFLO CR is a potential elevation of liver enzymes (in 2% of patients). Therefore, zileuton is contraindicated in patients with active liver disease or persistent hepatic function enzymes elevations greater than three times the upper limit of normal. Hepatic function should be assessed prior to initiating ZYFLO CR, monthly for the first 3 months, every 2–3 months for the remainder of the first year, and periodically thereafter.Neuropsychiatric events, including sleep disorders and behavioral changes, may occur with ZYFLO and ZYFLO CR. Patients should be instructed to notify their healthcare provider if neuropsychiatric events occur while using ZYFLO or ZYFLO CR.
Zileuton is a weak inhibitor of CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
and thus has three clinically important drug interactions, which include increasing warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
, theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, and propranolol levels. It has been shown to lower theophylline clearance significantly, doubling the AUC and prolonging half-life by nearly 25%. Because of theophylline's relation to caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
(both being a methylxanthine, and theophylline being a metabolite of caffeine), caffeine's metabolism and clearance may also be reduced, but there are no drug interaction studies between zileuton and caffeine. The R-isomer of warfarin metabolism and clearance is mainly affected by zileuton, while the S-isomer is not (because of metabolism via different enzymes). This can lead to an increase in prothrombin time.
Chemistry
Zileuton is an active oral inhibitor of the enzyme 5-lipoxygenase, which forms leukotrienes from arachidonic acidArachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
. The chemical name of zileuton is (±)-1-(1-Benzo[b]thien-2-ylethyl)-l-hydroxyurea.
The molecular formula of zileuton is C11H12N2O2S with a molecular weight of 236.29. The formulation from the manufacturer is a racemic mixture of R(+) and S(-) enantiomers.
Pharmacokinetics
Following oral administration zileuton is rapidly absorbed with a mean time to peak blood serumBlood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
concentration of 1.7 hours and an average half-life elimination of 2.5 hours. Blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
concentrations are proportional to dose, whereas the absolute bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is unknown.
The apparent volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
, with minor binding to alpha-1-acid glycoprotein.
Elimination of zileuton is primarily through metabolites in the urine (~95%) with the feces accounting for the next largest amount (~2%). The drug is metabolized by the cytochrome P450 enzymes: CYP1A2, 2C9, and 3A4.
Adverse effects
The most common adverse reactions reported by patients treated with ZYFLO CR were sinusitisSinusitis
Sinusitis is inflammation of the paranasal sinuses, which may be due to infection, allergy, or autoimmune issues. Most cases are due to a viral infection and resolve over the course of 10 days...
(6.5%), nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
(5%), and pharyngolaryngeal pain (5%) vs. placebo, 4%, 1.5%, and 4% respectively.
Drug interactions
Zileuton is a minor substrate of CYP1A2, 2C8/9, 3A4, and a weak inhibitor of CYP 1A2. The drug has been shown to increase the serum concentration or effects of theophyllineTheophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, propranolol, and warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
. It is advised that the doses of each medication be monitored and/or reduced accordingly.
Other interactions
The avoidance of alcoholAlcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
is recommended due to increase risk of CNS depression as well as an increase risk in liver toxicity. In addition, the herbal supplement St. John's wort may decrease the serum levels of zileuton.
Symptoms
Human experience of acute overdose with zileuton is limited. A patient in a clinical study took between 6.6 and 9.0 grams of zileuton immediate-release tablets in a single dose. Vomiting was inducted and the patient recovered without sequelae. Zileuton is not removed by dialysis.The oral minimum lethal doses in mice and rats were 500-4000 and 300–1000 mg/kg, respectively (providing greater than 3 and 9 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose, respectively). In dogs, at an oral dose of 1000 mg/kg (providing in excess of 12 times the systemic exposure (AUC) achieved at the maximum recommended human daily oral dose) no deaths occurred by nephritis was reported.
Treatment
Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted as required. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavageGastric lavage
Gastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...
; usual precautions should be observed to maintain the airway. A Certified Poison Control Center should be consulted for up-to-date information on management of overdose with ZYFLO CR.