GASTRIC PH INFLUENCES THE APPEARANCE OF DOUBLE PEAKS IN THE PLASMA CONCENTRATION-TIME PROFILES OF CIMETIDINE AFTER ORAL-ADMINISTRATION IN DOGS

The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted st ate, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, abso rption of cimetidine after a single dose in the fasted state was studi ed as a function of gastric pH in male beagle dogs to determine whethe r gastric pH plays a role in the double peak phenomenon and/or can acc ount for the decrease in bioavailability when antacids are coadministe red. The extent of absorption of cimetidine was not influenced signifi cantly by gastric pH, indicating that elevation of gastric pH is not t he cause of decreases in the bioavailability of cimietidine when it is administered with antacids. Distinct double peaks or plateaux were no ted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irr egular absorption behavior was observed in 2 of 6 profiles in the pH r ange of 3 to 5, while single peaks were observed in all 10 profiles wh en the gastric pH was maintained at pH greater than or equal to 5. It was concluded that gastric pH is a major factor in the generation of c imetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kin etic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH greater than or equal to 5, however , absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from var iations in gastric emptying as a function of pH and/or carryover effec ts of gastric pH into the upper intestine.