ReviewIn vitro trans-monolayer permeability calculations: often forgotten assumptions
Section snippets
pH
Many ionizable molecules coexist in both their charged and uncharged forms in solution. At physiological pH 7.4, most drug molecules are predominantly ionized. The pH partition hypothesis assumes that the uncharged form of a molecule might diffuse across lipid membranes, but that the charged form is impermeable. Lumenal pH values differ throughout the GI tract, therefore, the extent of permeation depends partly on where absorption takes place. The relationship between Papp and pH is an
Recommendations
Study of the literature suggests that the ideal intestinal in vitro permeability assay would have pH 6.0 and 7.4 in the donor wells, with pH 7.4 in the receiver wells (a two-pH combination could differentiate acids from bases and non-ionizables by the differences between the two Papp values) [2]. Furthermore, the receiver side would have 3% wt/vol BSA (or some sink-forming equivalent) to maintain a sink condition. The donor side may benefit from having a bile acid (i.e. taurocholic or
Conclusion
The choice of a test system always represents a compromise between high throughput with low predictive potential and low throughput with high predictive potential. Table 1 highlights mathematical and experimental techniques that should be taken into account when performing HTS and/or mechanistic studies. The introduction of radical changes to permeability studies is not the intention here; the intention is to make researchers, working within the industrial sector or academia, aware of how their
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