Permeability-pH Considerations

The effective permeability of ionizable molecules depends on pH, and the shapes of the permeability-pH profiles can be theoretically predicted when the pKa of the molecule is known, the pH partition hypothesis are valid, and the resistance of 

Lipid6 [Ref.] BBMC [30] MDCK [38] BBBe [37] BBM ModeF 20% Extract Lecithin 60% Extract Lecithin  

6PC = phosphatidylcholine, PE = phosphatidylethanolamine, PS = phosphatidylserine, PI = phosphati-dylinositol, Sph = sphingomyelin, FA = fatty acid, PA = phosphatidic acid, LPI = lyso-PI, CL = car-diolipin, LPC = Iyso-PC, CHO = cholesterol, CE = cholesterol ester, TG = triglycerides. 

CBB 1 — reconstituted brush-border membrane, rat (average of four studies). 

Said et al. [78] directly measured the acid microclimate on the surface of gastrointestinal tract (GIT) epithelial cells (intact with mucus layer) in rats. The pH on the apical (donor) side of the cells varied from 6.0 to 8.0, while the pH on the basolateral (acceptor) side was 7.4. Furthermore, the pH gradient between 

The effective permeability of ionizable molecules depends on pH, and the shapes of the permeability-pH profiles can be theoretically predicted when the pKa of the molecule is known [7]. The pH dependency of ionizable molecules is illustrated in Fig. 3.3 for a series of weak acids (A. Avdeef, not published). It is clear that if the wrong pH is used in screening the permeabilities of molecules, then highly promising molecules (e.g., probenecid Fig. 3.3) may be characterized as false negatives. The ideal pH to use for in vitro screening ought to reflect the in vivo pH conditions. 

Said et al. [32] directly measured the acid microclimate on the surface of gas- 

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