Increased membrane permeation and blood concentration of 6‐carboxyfluorescein associated with dysfunction of paracellular route barrier in the small intestine of ulcerative colitis model rats

Abstract

In the colon of patients with ulcerative colitis (UC), decreased function of the paracellular barrier, especially hypofunction of the tight junction, is associated with pathological conditions. However, there has been no report to date on the function of tight junctions in the small intestine. Here, we focused on the barrier function of the small intestine, especially in tight junctions, and compared it with that of the colon. Dextran sulfate sodium (DSS) was used to induce ulcerative colitis in rats in order to evaluate the function of the paracellular barrier in the jejunum, ileum, and colon. An in vitro diffusion chamber method was used to evaluate membrane resistance, which is an index of tight junction function and mucosal permeability, using 6-carboxyfluorescein (6-CF), a paracellular marker. In the jejunum and colon, with decrease of membrane resistance in the DSS group, mucosal permeability increased, whereas no marked difference was observed in the ileum. In the in situ closed-loop method, absorption of 6-CF from the jejunum was higher than that from the ileum.Immunohistochemical staining of claudin-4 showed heterogeneous attenuation of claudin-4 in the jejunum. Pharmacokinetic parameters were calculated from the blood concentration after intravenous injection and oral administration of 6-CF. In the DSS group, there was a delay in the elimination phase, suggesting a decrease in renal function, and an increase in maximum blood concentration, associated with an increased absorption rate constant. The increased absorption and decreased renal function due to decreased paracellular barrier function in the small intestine and colon may cause fluctuations in drug efficacy and side effects. K E Y W O R D S membrane resistance, paracellular route, small intestine, tight junction, ulcerative colitis

Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

“…Increased membrane permeability may also contribute to the greater AUC of a drug in DSS rats. Dysfunction of the epithelial paracellular barrier and increase in mucosal permeability in the small intestine and colon contribute to increased absorption and result in significantly greater AUC of 6-carboxyfluorescein ( Kumagai et al ., 2020 ) and phenytoin ( Kusunoki et al ., 2017 ) in the DSS rat model.…”