Zileuton Theophylline

Administration of zafirlukast and aspirin increases plasma levels of zafirlukast, When zafirlukast is administered with warfarin, there is an increased effect of the anti coagulant. Administration of zafirlukast and theophylline or erythromycin may result in a decreased level of zafirlukast. Administration of montelukast with other drugs has not revealed any adverse responses. Administration of montelukast with aspirin and NSAIDs is avoided in patients with known aspirin sensitivity. Administration of zileuton with propranolol increases the activity or the propranolol with theophylline increases serum theophylline levels and with warfarin may increase prothrombin time (PT). A prothrombin blood test should be done regularly in the event dosages of warfarin need to be decreased. 

Use of zileuton is uncommon due to the need for dosing four times a day, potential drug interactions, and the potential for hepatotoxicity with the resulting need for frequent monitoring of liver enzymes. In patients started on zileuton, serum alanine aminotransferase concentrations should be monitored before treatment begins, monthly for the first 3 months, every 2 to 3 months for the remainder of the first year, and then periodically thereafter for as long as the patient continues to receive the medication. Zileuton also inhibits the cytochrome P-450 (CYP) mixed function enzyme system and has been shown to decrease the clearance of theophylline, R-warfarin and propranolol.34... 

Use of zileuton is limited due to the potential for elevated hepatic enzymes (especially in the first 3 months of therapy), and inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin). Serum alanine aminotransferase should be monitored before treatment and then periodically thereafter. 

Drugs that may be affected by zileuton include propranolol, terfenadine, theophylline, and warfarin. 

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small percentage of patients taking zileuton. Serum Uver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma concentrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease. 

Theophylline [the OFF i lin] is a bronchodilator that relieves airflow obstruction in chronic asthma, and decreases the symptoms of the chronic disease. Previously the main-stay of asthma therapy, theophylline has been largely replaced with (3-agonists and corticosteroids. Theophylline is well absorbed by the gastrointestinal tract, and several sustained-release preparations are available. The drug has a narrow therapeutic window, and an overdose of the drug may cause seizures or potentially fatal arrhythmias. Further, theophylline interacts adversely with many drugs. See pp. 450-451 for a description of newly approved drugs, zileuton, zafirlukast, and montelukast. 

In -4—5% of patients taking zileuton, there is an elevation in hepatic transaminases, generally within the first 2 months of therapy. Zileuton decreases the steady-state clearance of theophylline, substantially increasing its plasma concentrations. Zileuton also decreases warfarin clearance. 

A2 Cimetidine, fluoroquinolones, grapefruit juice, macrolides, isoniazid, zileuton Acetaminophen, clozapine, haloperidol, theophylline, tricyclic antidepressants, (R)-warfarin... 

Zileuton raises theophylline levels and increases the incidence of adverse effects. 

In a double-blind, crossover study, 13 healthy subjects were given 200 mg of theophylline Slo-Phyllin) four times daily for 5 days and either zileuton 800 mg twice daily or a placebo. Zileuton caused a 73% rise in the mean steady-state peak serum levels of theophylline (from 12 to 21 mg/L), a 92% increase in its AUC, and halved its apparent plasma clearance. During the use of zileuton the incidence of adverse effects increased (headache, gastrointestinal effects), which was attributed to theophylline toxicity, and this caused 3 of the original 16 subjects to withdraw from the study. ... 

Not fully established but it seems highly likely that zileuton inhibits the metabolism of the theophylline by the cjdochrome P450 enzymes (probably the isoenzymes CYPl A2 and CYP3A) so that its serum levels rise. 

Information is limited but the interaction appears to be established and of clinical importance. Concurrent use need not be avoided but monitor theophylline levels and reduce the dosage of theophylline as necessary. The report quoted above suggests that a typical asthma patient may initially need the theophylline dosage to be halved, and this dose reduction is recommended by the US manufacturers. Similarly, the dose of theophylline should be reduced if it is given to a patient already taking zileuton, and adjusted according to theophylline levels. This is based on the results of a study in over 1000 patients taking zileuton 600 mg four times daily without apparent problems when this course of action was followed. ... 

Granneman GR, Braeckman RA, Locke CS, Cavanaugh JH, Dube LM, Awni WM. Effect of zileuton on theophylline pharmacokinetics. ClmPhcamacokinet 995) 29 (Suppl 2), 77-83. 

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