Effect of mucus layer on the transcellular absorption of lipophilic drugs in rat small intestine

Abstract

PurposeThe mucus layer, which is adjacent to the intestinal wall, is considered to be a physiological barrier to intestinal drug absorption, since a drug must diffuse through this lipophilic layer prior to permeation across the intestinal epithelial cells. Thus, mucus layer permeation is suggested to be a rate‐limiting step in the intestinal absorption of lipophilic drugs. The major glycoprotein components of the mucus layer are mucins, which presumably play a pharmaceutical role in intestinal drug absorption, however, there have been no reports that describe the contribution of mucins to intestinal drug absorption at the molecular level. In this study, we examined the involvement of the mucus layer in the intestinal permeability of various lipophilic drugs in rat small intestine. Furthermore, we evaluated the regional distributions of mucins (MUCs) in rat gastrointestinal tract and explored the relationship between the effect of the mucus layer on passive transcellular transport and the expression pattern of mucins.MethodsDrug permeation experiments were conducted using the in vitro sac method. The amount of mucus glycoproteins liberated from the intestinal wall were determined by the alcian blue method. The mRNA and protein expression levels of mucins were evaluated by quantitative real‐time RT‐PCR (qPCR) and Western blotting, respectively.Results and DiscussionThe membrane permeability of the lipophilic drugs in the rat gastrointestinal tract was increased by pretreatment with dithiothreitol (DTT), which is commonly used as a mucus remover, and the alternation was remarkable in the upper part of the small intestine. Furthermore, the enhancing effects of DTT tended to be pronounced on the permeability of drugs with higher log D values in the case of neutral drugs with non‐dissociable groups. These results indicated that the effect of the mucus layer on intestinal permeability depends on the log D values and the physiological charge of the compound. On the other hand, the mRNA expression analysis of MUC genes revealed that the intestinal expression of MUC5AC is considerably higher in the duodenum, and those of MUC1, MUC2, and MUC3A are gradually increased toward the lower intestine in rats. Furthermore, Western blotting showed abundant MUC5AC protein in the mucus solution liberated from jejunum, but not from ileum and colon by the treatment with DTT. Therefore, these results suggest that rMUC5AC is involved in the absorption of lipophilic drugs in the upper part of rat small intestine.ConclusionsMUC5AC could be involved in the barrier function to limit the transcellular permeation of hydrophobic drugs in the upper part of the gastrointestinal tract.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.