PAMPA--a drug absorption in vitro model 8. Apparent filter porosity and the unstirred water layer.

Abstract

In the parallel artificial membrane permeability assay (PAMPA), if more lipid is used than needed to fill all the pores of a microfilter, the excess lipid layer on both sides of the lipophilic filter increases the "apparent" porosity, epsilon(a), of the filter. The specific resistance of the artificial membrane barrier is lowered with increasing lipid excess. If this effect is not recognized, and the uncorrected value of filter porosity, epsilon, is used, then the calculated intrinsic permeability and the unstirred water layer (UWL) permeability coefficient of the permeating molecule can be significantly overestimated, resulting in underestimates of the thickness of the unstirred water layer. Unstirred water layer corrections are important in pharmaceutical research for in vitro-in vivo correlations aimed at predicting oral absorption and blood-brain barrier penetration characteristics of lead candidate compounds. The novel concept of the apparent porosity is introduced, described, and its utility demonstrated with the drugs diclofenac, desipramine, caffeine, and piroxicam. The PAMPA data of Wohnsland and Faller [J. Med. Chem. 44 (2001) 923] is taken as an example, where the reported extraordinarily efficient stirring is thought to be better explained in terms of normal stirring when apparent porosity is taken into account in the calculation of the effective permeability coefficient.