Oral absorption of histamine-2 receptor antagonists.

Abstract

Absorption of cimetidine after a single oral dose in the fasted state was studied as function of gastric pH in male beagle dogs to determine whether alteration in pH plays a role in the double peak phenomenon and/or the poor bioavailability following concurrent administration of antacids. In addition, the intestinal uptake mechanism of cimetidine and ranitidine was characterized and uptake from different intestinal sites compared at pH 6 in rats to evaluate any contribution of site specificity of absorption to the double peak phenomenon. Following oral administration of cimetidine in dogs, distinct double peaks or plateaux were noted in the plasma profiles in eight out of ten studies when gastric pH was below 3 while single peaks were observed in all the cases whenever gastric pH was maintained above 5. At higher gastric pH, there was a significant increase in the maximum concentration while time to reach maximum concentration was shortened (p $<$ 0.05). There was a change in the kinetic order as well as the rate of absorption of cimetidine with change in gastric pH. Below pH 5, absorption occurred by either an apparent zero-order or a more complex kinetic process involving at least two components to the absorption phase. Above gastric pH 5, first order absorption was noted. However, increasing the gastric pH had no significant effect on the area under the cimetidine plasma concentration curves indicating that extent of absorption was not affected by gastric pH. In vitro everted intestinal ring studies indicated that cimetidine and ranitidine are absorbed by a predominantly passive diffusion process over a wide concentration range. There was no significant difference in cimetidine uptake rate from duodenum, jejunum or ileum. Colonic uptake rate of cimetidine (82 nmoles/g/min/mM) was about 70% of jejunal uptake (116 nmoles/g/min/mM). There was no significant difference between duodenal and jejunal uptake rates of ranitidine, but ileal uptake rate was greater (p $<$ 0.05). Ranitidine uptake rate from the colon (63 nmoles/g/min/mM) was significantly lower than jejunal uptake rate (82 nmoles/g/min/mM). These studies indicate that gastric pH is a major factor influencing the rate of absorption and the occurrence of double peaks in the plasma profiles of cimetidine. (Abstract shortened by UMI.).