Theophylline + Zileuton - Drug Interactions

Zileuton raises theophylline levels and increases incidence ofadverse effects

In a double-blind,crossover study, 13 healthy subjects were given 200mg of theophylline (Slo-Phyllin) four times daily for 5 days and either zileuton 800mg twice daily or a placebo. Zileuton caused a 73 % rise in 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 use of zileuton incidence of adverse effects increased (headache, gastrointestinal effects), which was attributed to theophylline toxicity, and this caused 3 of original 16 subjects to withdraw from study (See reference number 1).

Not fully established but it seems highly likely that zileuton inhibits metabolism of theophylline by cytochrome P450 enzymes (probably isoenzymes CYP1A2 and CYP3A) so that its serum levels rise

Information is limited but interaction appears to be established and of clinical importance. Concurrent use need not be avoided but monitor theophylline levels and reduce dosage of theophylline as necessary. The report quoted above suggests that a typical asthma patient may initially need theophylline dosage to be halved, and this dose reduction is recommended by US manufacturers (See reference number 2). Similarly, dose of theophylline should be reduced if it is given to a patient already taking zileuton, and adjusted according to theophylline levels (See reference number 2). This is based on results of a study in over 1000 patients taking zileuton 600mg four times daily without apparent problems when this course of action was followed (See reference number 1).

Granneman GR,Braeckman RA, Locke CS, Cavanaugh JH, Dubé LM, Awni WM. Effect ofzileuton on theophylline pharmacokinetics. Clin Pharmacokinet (1995) 29 (Suppl 2), 77–83.

Zyflo (Zileuton). Critical Therapeutics Inc. US Prescribing information,November 2005.