Intestinal mucosa barrier function

When a drug has dissolved in the GI fluids and is present in solution at the site of absorption it has to pass a biological barrier, that is, the enterocytes lining the gut wall, in order to be absorbed into the body. The absorptive flux (J) can be described as a function of the permeability of the intestinal mucosa to the drug (Peff), the surface area available for absorption (SA), and the concentration gradient (AC) across the mucosa (e.g., [6], Eq. 2)... 

Passive transcellular transport across the intestinal epithelium involves three discrete steps (1) uptake across the apical membrane, (2) diffusion through the cytoplasm, and (3) efflux across the basolateral membrane. Occasionally, drug molecules without favorable physicochemical properties traverse the intestinal epithelium using endogenous membrane transporters.6-8 In addition, the intestinal mucosa, with its numerous drug-metabolizing enzymes and efflux transporters, such as P-glycoprotein (Pgp), functions as a biochemical barrier.9... 

Comparison of their rate of onset and recovery of a treated mucosa has been made [37]. Fatty acids have strong and fast reactivity and allow for a fast recovery of the barrier function. Bile salts and salicylates are moderate, fast-acting agents with fast barrier-function recovery. Strong surfactants and chelators have strong or moderate reactivity and a slow recovery of barrier function. Solvents like dimethylsulfoxide and ethanol have moderate reactivity and act primarily as agents to improve drug miscibility in an aqueous environment. The enhancers listed above are also effective in the small intestine [22]. Enhancers that are more colon specific include ethylaceto-acetate, which must be first metabolically transformed to enamine [38]. 

In recent years, it has been recognized that P-Gp can significantly contribute to the barrier function of the intestinal mucosa. P-Gp is an integral membrane... 

Several in vitro works conclude that berberine can ameliorate intestinal epithelial tight junction damage induced by the release of proinflammatoiy cytokines [65, 66]. This effect has been attributed to the downregulation of the NF-kB and myosin light chain kinase pathway. These findings suggest that this crxnpound may help to restore barrier function in injured intestinal mucosa [65, 66]. 

Lennernas s group at Uppsala has performed extensive studies to confirm the validity of this in vivo experimental set-up at assessing the rate and the extent of drug absorption. Recovery of PEG 4000 (a non-absorbable marker) is more than 95%, which indicates that the absorption barrier is intact. In addition, maintenance of functional viability of the mucosa during perfusion has been demonstrated by the rapid transmucosal transport of D-glucose and L-leucine. Estimation of absorption half-lives from the measured Pefr agree well with half-lives derived from oral dose studies in humans (i.e. physiologically realistic half-lives). Human Peff estimates are well correlated with the fraction absorbed in humans, and served as the basis for BCS development, and hence the technique is ultimately the benchmark by which other in situ intestinal perfusion techniques are compared. The model has been extensively used to... 

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