Cimetidine absorption and elimination in rat small intestine.

The purpose of this study was to determine the characteristics of intestinal absorption and metabolism of cimetidine. The initial finding of the appearance of cimetidine sulfoxide in rat and human jejunum from cimetidine perfusions had prompted an isolation of mucosal membrane transport and enterocyte metabolism contributions in earlier membrane vesicle and microsomal studies, respectively. In this report, perfusion studies in rat small intestine detail regional differences in intestinal elimination. Cimetidine S-oxide appears to a significantly greater extent in the jejunum compared with the ileum. Jejunal metabolite appearance is shown to be a function of the pH-dependent intracellular uptake of cimetidine. Cimetidine permeability decreases with increasing perfusion concentration in both jejunum and ileum. Similar permeability magnitudes and concentration dependence are observed in both regions. Perfusion studies with inhibitors of cimetidine mucosal transport and inhibitors of microsomal S-oxidation provide an inhibition profile suggesting that jejunal cimetidine permeability decreases with increasing intracellular cimetidine concentration. The data support a reduction in paracellular cimetidine absorption as controlled by intracellular cimetidine. This inference is drawn on the basis of mass balance. Because significant appearance of cimetidine S-oxide was previously found in human jejunal perfusions, this region-dependent intestinal elimination process detailed in rats may be relevant to drug plasma-level double peaks observed in clinical studies. Saturation of jejunal metabolism at typical oral doses may limit paracellular absorption of cimetidine in the jejunum and contribute to the double peak phenomenon and to absorption variability.