Secondary peaks in oral concentration-time profiles following ranitidine administration may be due to discontinuous absorption along the gastrointestinal tract, postabsorptive storage and release, and/or enterohepatic recirculation (ER). The suitability of the rat as an animal model for studying mechanisms of the double peaks, and the relationship between ER and the occurrence of secondary peaks in ranitidine concentration-time profiles, were examined in the present investigation. Male Sprague-Dawley rats received ranitidine by oral gavage (50 mg/kg), and blood was collected at various times for 6 hr after dosing. Eight rats with chronic bile duct and jugular vein cannulae received ranitidine with bile flow intact or interrupted in a randomized complete cross-over design. Bile duct-cannulated (BDC) rats were divided into two groups: four rats received ranitidine immediately after bile flow interruption, and four rats received ranitidine 3 hr after bile flow interruption. Blood and bile were analyzed for ranitidine by HPLC. The area under the ranitidine concentration-time profile, the maximum serum ranitidine concentration, the time of maximum concentration, the fraction of ranitidine absorbed at each blood sample, biliary clearance, and the percentage of the dose recovered in bile as ranitidine were determined. Results indicated that the rat is an appropriate model for studying mechanisms responsible for the double peaking phenomenon. Multiple peaks or plateaus were observed in the ranitidine concentration-time profiles of all rats after oral administration with bile flow intact. Secondary peaks were evident in only two concentration-time profiles of BDC rats when bile flow was interrupted. Less than 3% of the dose was recovered in the bile as ranitidine or metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)