Regulation of paracellular absorption of cimetidine and 5-aminosalicylate in rat intestine

Purpose. Isolating the relative contributions of parallel transcellular and paracellular transport to the intestinal absorption of small hydrophilic m olecules has proven experimentally challenging. In this report, lumenal app earance of drug metabolite is utilized as a tool to assess the contribution of paracellular paracellular transport to the absorption of cimetidine and 5-aminosalicylate (5ASA) in rat small intestine. Methods. Steady-state intestinal absorption and elimination of cimetidine a nd 5ASA were studied in single-pass intestinal perfusions in rats. Results. Both drugs were metabolized in intestinal epithelia with subsequen t metabolite secretion into the intestinal lumen. Jejunal cimetidine absorp tion decreased with increasing perfusion concentration while the ratio of l umenal metabolite to lumenal drug loss increased. Cimetidine uptake at perf usion concentrations above 0.4 mM resulted in over 80% drug elimination int o the jejunal lumen. Inhibition of intracellular metabolism of cimetidine b y methimazole did not alter epithelial uptake but totally abolished transep ithelial cimetidine fur indicating an elevation of intracellular cimetidine . Similarly, co-perfusion of 5ASA with cimetidine and methimazole totally a bolished 5ASA absorption but increased lumenal levels of N-acetyl 5ASA indi cating an increase in intracellular uptake of 5ASA. Conclusions. Cimetidine and 5ASA absorption across rat jejunal epithelia ar e exclusively paracellular. Elevation of intracellular cimetidine, inferred from mass balance considerations, restricts paracellular transport of both drugs.