Cimetidine absorption and elimination in rat small intestine

The purpose of this study was to determine the characteristics of intestina l absorption and metabolism of cimetidine. The initial finding of the appea rance of cimetidine sulfoxide in rat and human jejunum from cimetidine perf usions had prompted an isolation of mucosal membrane transport and enterocy te metabolism contributions in earlier membrane vesicle and microsomal stud ies, 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-de pendent intracellular uptake of cimetidine. Cimetidine permeability decreas es with increasing perfusion concentration in both jejunum and ileum. Simil ar permeability magnitudes and concentration dependence are observed in bot h regions. Perfusion studies with inhibitors of cimetidine mucosal transpor t and inhibitors of microsomal S-oxidation provide an inhibition profile su ggesting that jejunal cimetidine permeability decreases with increasing int racellular cimetidine concentration. The data support a reduction in parace llular cimetidine absorption as controlled by intracellular cimetidine. Thi s inference is drawn on the basis of mass balance. Because significant appe arance of cimetidine S-oxide was previously found in human jejunal perfusio ns, this region-dependent intestinal elimination process detailed in rats m ay be relevant to drug plasma-level double peaks observed in clinical studi es. Saturation of jejunal metabolism at typical oral doses may limit parace llular absorption of cimetidine in the jejunum and contribute to the double peak phenomenon and to absorption variability.