zileuton

Zileuton
Systematic (IUPAC) name
N-​[1-​(1-​benzothien-​2-​yl)​ethyl]-​N-​hydroxyurea
Identifiers
CAS number	111406-87-2
ATC code	none
PubChem	60490
DrugBank	APRD00265
Chemical data
Formula	C11H12N2O2S
Mol. mass	236.291 g/mol
Pharmacokinetic data
Bioavailability	Not yet established
Protein binding	93%
Metabolism	Hepatic (CYP1A2, CYP2C9 and CYP3A4-mediated)
Half life	2.5 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(US)
Legal status	℞-only(US)
Routes	Oral

Zileuton (INN) is an asthma drug. It blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway. Zileuton was introduced in 1997 by Abbot Laboratories and is now marketed by Critical Therapeutics under the brand name ZYFLO. The original four-times-per-day immediate-release formulation of zileuton, known as ZYFLO IR, was, as of March 1, 2008, discontinued and replaced by ZYFLO CR.^[1]

Pharmacotherapy

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 bronchospasm in acute asthma attacks. Therapy with zileuton can be continued during acute exacerbations of asthma. 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 total daily dose of 2400 mg.

Related compounds include montelukast (Singulair) and zafirlukast (Accolate). These two compounds block the leukotriene receptor, while zileuton blocks the synthesis of leukotrienes.

Research on mice suggests that Zileuton used alone or in combination with imatinib may inhibit chronic myeloid leukemia (CML). Lethal Cancer Knocked Down By One-two Drug Punch ScienceDaily (June 8, 2009).

Contraindications and warnings

Zileuton frequently causes liver enzyme elevations and thus are contraindicated in patients with active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal. Liver enzymes should be monitored prior to administering zileuton and repeated on a regular basis while patients are on the medication.

Zileuton is a weak inhibitor of CYP1A2^[2] and thus has several clinically important drug interactions, such as inhibiting warfarin and theophylline metabolism. It lowered 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.^[3] 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.^[4]

Chemistry

Zileuton is an active oral inhibitor of the enzyme 5-lipoxygenase, which forms leukotrienes from arachidonic acid. 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.^[5]

Pharmacokinetics

Following oral administration zileuton is rapidly absorbed with a mean time to peak serum concentration of 1.7 hours and an average half-life elimination of 2.5 hours. Plasma concentrations are proportional to dose, whereas the absoulte 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.^[5]

Adverse effects

The most common adverse event associated with zileuton is headache (25%). Other frequently occurring adverse reactions include: pain (8%), dyspepsia (8%), nausea (6%), abdominal pain (5%), leukopenia (1%), ALT (alanine transaminase) increase (2%), asthenia (4%), and myalgia (3%).^[6]

Interactions

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 theophylline, propranolol, and warfarin. It is advised that the doses of each medication be monitored and/or reduced accordingly.

Other interactions

The avoidance of alcohol 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.^[6]

Other neuropschiatric events noted postmarketing include agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior [including suicide], and tremor,

Overdose/toxicology

Symptoms

In humans symptoms of overdose are limited. The minimum oral 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). No deaths occurred, but nephritis was reported 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). In the case of a suspected overdose a certified poison control center should be consulted for updated information regarding management of overdose with zileuton.

Treatment

In the case of an overdose, patients should receive supportive care with treatment given only symptomatically. If indicated, the drug can be eliminated through emesis or gastric lavage with proper measures to ensure airway patency.^[6]

See also

• Lipoxygenase inhibitor

External links

• Zyflo (manufacturer's website)
• Zileuton (patient information)

References