title: Safety: cimetidine and concomitant theophylline or warfarin--drug interactions and their implications.
abstract: Theophylline and warfarin are two drugs whose interactions with cimetidine may have clinically significant effects. Therefore, recent efficacy studies comparing cimetidine 800 mg at bedtime (HS) with 300 mg QID included studies of interactions between cimetidine and these agents. Thirty healthy men were stratified into three age groups: 18 to 35, 36 to 53, and 54 to 70 years and were given 300 mg QID of anhydrous theophylline sustained-action tablets. When steady state was reached (nine days), cimetidine was begun concomitantly in a dosage of 300 mg QID or 800 mg HS for ten days. Three days after cimetidine was started, morning and evening trough theophylline serum levels were monitored. The area under the theophylline serum level-time curve (AUC) was determined on days 5 and 10 of the cimetidine regimen. Upon discontinuation of cimetidine, morning and evening trough serum theophylline levels were measured to determine when all subjects had returned to precimetidine steady-state conditions. A new baseline AUC was then obtained and concomitant administration of the alternate cimetidine regimen was started. Serum theophylline levels were measured as with the first cimetidine regimen. Theophylline was continued for an additional ten days with monitoring of trough levels, after the second cimetidine regimen was completed. AUC was measured after precimetidine steady-state conditions were reached. Steady-state theophylline levels were increased less by the 800-mg HS cimetidine regimen than by the 300-mg QID regimen. Although both regimens significantly (P less than 0.05) increased the theophylline AUC and maximum serum concentration (Cmax) in all age groups, the effect of cimetidine 800 mg HS was significantly less for all subject data combined and particularly for the oldest groups of subjects, indicating that the theophylline-cimetidine interaction is age-related. New theophylline steady-state levels were achieved by day 5 of concomitant cimetidine administration, and precimetidine theophylline serum trough levels, Cmax, and AUC were observed five days after discontinuation of both cimetidine regimens. The effects of the same two cimetidine regimens on the pharmacodynamics and pharmacokinetics of warfarin were also evaluated in 25 patients stabilized on anticoagulant therapy. The preliminary data indicate that patients with a baseline prothrombin time ratio (PTR) of less than 2.0 would not be expected to exceed a PTR greater than 2.5 after two weeks of concomitant administration of cimetidine at either dosage.(ABSTRACT TRUNCATED AT 400 WORDS)
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002927:Cimetidine / Q000008:administration & dosage / Q000378:metabolism*; D004347:Drug Interactions; D006635:Histamine H2 Antagonists / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism*; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D006635:Histamine H2 Antagonists; D014859:Warfarin; D002927:Cimetidine; D013806:Theophylline