Inhibition of theophylline metabolism by long-term allopurinol administration

Administration of an oral dose of allopurinol (300 mg every 12 hr) for 14 consecutive days increased the mean theophylline area under the curve (AUC) 27% and mean theophylline half-life (t1/2) 25%, whereas the mean theophylline clearance (Cl) decreased 21%. Allopurinol did not alter either apparent volume of distribution (aVd) or gastrointestinal absorption (Cmax and tmax) of theophylline. After 28 consecutive days of allopurinol administration, theophylline disposition was the same as that on day 14. Thus, given in a dose of 300 mg every 12 hr for 14 or 28 days, allopurinol inhibits theophylline metabolism, despite the failure of allopurinol in lower doses given for only 7 days to alter theophylline disposition. These results emphasize the need to investigate several different doses and durations of administration within therapeutic ranges before firm conclusions can be drawn concerning the influence of one drug on the disposition of another.