Membrane Transport of Drugs in Different Regions of the Intestinal Tract of the Rat

Abstract

Regional permeability coefficients of 19 drugs with different physicochemical properties were determined using excised segments from three regions of rat intestine: jejunum, ileum, and colon. The results are discussed in relation to the characteristics of the drug, i.e., MW (range 113-1071 Da), pKa, log D (octanol/water at pH 7.4) (range -3.1 to +2.4), and the regional change in the properties of the epithelial membrane. There was a significant decrease in permeability to hydrophilic drugs and a significant increase in permeability for hydrophobic drugs aborally to the small intestine (P < 0.0001). A good correlation could be obtained between MW and permeability coefficients of hydrophilic drugs. The correlation established between the apparent permeability coefficients and the partition coefficients of the drugs was sigmoidal in shape in all three regions and a log D between 0 and 2.5 predicts high permeability values. These permeability data are unique since they result from a diversity of chemical structures with different physicochemical characteristics and a variety of transport mechanisms and they are not influenced by interlaboratory differences. The large regional permeability database in the present study shows the utility of the Ussing chamber technique as a valuable predictive tool for human in vivo data. In addition, the regional permeability profiles obtained suggest a coupling between drug structure and the functional changes of the membrane, which might be useful for selecting a compound for an extended release formulation.

Resolution of P‐glycoprotein and non‐P‐glycoprotein effects on drug permeability using intestinal tissues from mdr1a (−/−) mice

“…The values obtained for propranolol and mannitol permeability in unstripped mouse ileum are very similar to those reported for stripped rat intestine (Ungell et al, 1998) suggesting that the presence of an intact muscle layer in mouse ileum has no signi®cant e ect on passive permeability.…”

“…Propranolol, which has been shown to be highly permeable across intestine (Ungell et al, 1998) was used to assess the inherent passive transcellular permeability of mouse tissues. Propranolol was added to the donor chamber at a concentration of 100 mM with 0.2 mCi.ml 71 [ 3 H]-propranolol and samples were taken from the receiver chamber every 40 min for up to 4 h. For analysis, P app values were averaged over 4 h (six 40 min¯ux periods).…”

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

“…2). Colonic mucosae basal TEER values were 112 ± 32 Ω cm 2 (n = 29), again within the accepted range (29) In the presence of FITC-tripeptides, colonic TEER showed a small decrease of 9% over 120 min, but this was not different from controls. Addition of C 10 and uC 11 significantly decreased TEER, to just 3% and 8% of basal values respectively from between 5-120 min compared to tissues exposed to FITC-tripeptides alone (Fig.…”

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…It has been suggested that due to a reduced SA and higher abundance of tight junctions (i.e. assumed smaller paracellular area) in the colonic membrane, intestinal permeability and possibly absorption should be reduced compared to that in the SI (4,5,22,25,66,67). This was appropriately captured when the predictions were made using P eff,int , estimated by both M2 and M3, without affecting the overall f abs predictions (Figs.…”