Membrane transport of drugs in different regions of the intestinal tract of the rat.
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.
Ungell
A L
AL
Drug Delivery Research, Astra Hässle Ab, Mölndal, Sweden. anna-lena.ungell@hassle.se.astra.com
Nylander
S
S
Bergstrand
S
S
Sjöberg
A
A
Lennernäs
H
H
D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D010539:Permeability; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley