Zileuton Warfarin

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. 

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... 

Warfarin Zileuton R t S o Possibly altered metabolic clearance of R t 77... 

Zileuton slightly increases the anticoagulant effects of warfarin and slightly increases It-warfarin levels, but this probably has little clinical relevance. 

In a placebo-controlled study, zileuton 600 mg every 6 hours for 6 days or placebo was given to healthy subjects who had been stabilised on racemic warfarin to achieve prothrombin times of 14 to 18 seconds for one week. The zileuton had no effect on the pharmacokinetics of 5-warfarin, but the R-warfarin AUC rose by 22%, and its clearance fell by 15%. The mean prothrombin times increased by 2.3 seconds (morning) and 2 seconds (evening) in the zileuton group. The corresponding increases in the placebo group were 0.7 and 0.2 seconds, respectively. ... 

It seems likely that zileuton inhibits the metabolism ofR-warfarin, probably by the cytochrome P450 isoenzyme CYP1A2. ... 

Awni WM, Hussein Z, Granneman PattersonKJ, Dube LM, Cavanaugh JH. Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans. ClinPharmacokinet ( 995) 29 (Suppl 2), 67-76. 

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