Permeability and the pH-partition hypothesis

in the first instance, the plasma membrane is considered to be a strip of lipoidal material, homogeneous in nature and with a defined thickness, one must assume that only lipid-soluble agents will pass across this barrier. As most dmgs are weak electrolytes it is to be expected that the unionised form (U) of either acids or bases, the lipid-soluble species, will diffuse across the membrane, while the ionised forms (1) will be rejected. This is the basis of the pH-partition hypothesis in which the pH dependence of drug absorption and solute transport across membranes is considered. The equations of Chapters 3 and 5 are relevant here. 

For weakly acidic dmgs such as acetylsali-cylic acid (aspirin) and indometacin, the ratio of ionised to unionised species is given by the equations 

One can calculate from these equations (and equations 3.70-3.73) the relative amounts of absorbable and nonabsorbable forms of a dmg substance ([U] and [1], respectively), given the prevailing pH conditions in the lumen of the gut or the site of absorption. The profiles for unionised dmg (%) versus pH for several dmgs are given in Fig. 9.5. In very broad terms, one would expect acids to be absorbed from the stomach and bases from the intestine. 

A comparison of the intestinal absorption of several acids and bases at several pH values (Table 9.2) indicates the expected trend. Surprisingly, however, it will be seen that salicylic acid is absorbed from the rat intestine at pH 8, although with a pK of 3.0 it is vir-mally completely ionised at this pH. There are two explanations one is that absorption and 

In attempts to explain away such discrepancies between theoretical prediction and observed results we have already hinted that a local pH exists at the membrane surface which differs from the bulk pH (see below). This local pH is due to the attraction of hydrogen ions by the negative groups of membrane components so that, in the intestine, while the bulk 

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