Twelve healthy non-smokers (7M and 5F) completed a balanced three-way crossover investigation designed to characterise the influence of oral cimetidine (800 mg), ranitidine (300 mg) and placebo pretreatment for 7 days on the pharmacokinetics of a 250 mg single oral dose of theophylline. The oral clearance of theophylline after ranitidine pretreatment, 4.55 +/- 1.69 l/h (mean +/- SD) was indistinguishable from that after placebo, 4.78 +/- 1.96 l/h, but cimetidine was associated with a significant 21% reduction in theophylline clearance, 3.58 +/- 1.07 l/h (P = 0.006). There was a correspondingly significant increase in the terminal half-life of theophylline following cimetidine, 6.11 +/- 1.29 h (P = 0.017), compared with 5.05 +/- 1.43 h and 4.88 +/- 1.45 h for placebo and ranitidine, respectively. There was no change in maximum theophylline concentration or time to maximum but following cimetidine the plasma theophylline levels between 4 and 12 hours were 15-50% higher than following placebo (P less than 0.002). These data indicate a significant interaction between 800 mg cimetidine given once daily and theophylline which is likely to be the result of enzyme inhibition. Once-daily dosing with 300 mg ranitidine had no significant effect on theophylline pharmacokinetics.