EFFECTS OF CIMETIDINE AND RANITIDINE ON THE PHARMACOKINETICS OF A CHRONOTHERAPEUTICALLY FORMULATED ONCE-DAILY THEOPHYLLINE PREPARATION (UNIPHYL(R))

The effects of cimetidine and ranitidine on the steady-state pharmacok inetics, safety, and efficacy of a chronotherapeutically formulated (C TF), once-daily theophylline preparation (Uniphyl(R)) were evaluated i n 12 adult patients with asthma. In this randomized, double-blind, thr ee-way crossover study, patients received a fixed dose of CTF-theophyl line and concurrent cimetidine, ranitidine, or placebo for a period of 7 days each. Asthma symptoms, drug side effects, and beta2-agonist in haler use were recorded daily. Venous blood sampling for pharmacokinet ic assessment was done over a complete dosing interval on day 7 of eac h phase. Coadministration of cimetidine, but not ranitidine, was assoc iated with a significant decrease in the apparent oral clearance of th eophylline (2.47 +/- 0.91 vs 1.85 +/- 0.63 L/hr; P=0.004) and increase s in the theophylline area under the curve (233.48 +/- 58.99 vs 307.43 +/- 79.07 mg/L/hr; P=0.003), peak concentration (13.2 +/- 2.8 vs 16.7 +/- 3.7 mg/L; P= 0.002), and trough concentration (6.4 +/- 2.5 vs 9.0 +/- 3.0 mg/L; P=0.008). Despite the changes in theophylline pharmacok inetic parameters during cimetidine treatment, no significant differen ces in asthma symptom scores or side effects were seen when once-daily CTF-theophylline was administered concomitantly with cimetidine, rani tidine, or placebo.