An evaluation of the relative roles of the unstirred water layer and receptor sink in limiting the in-vitro intestinal permeability of drug compounds of varying lipophilicity

The roles of the unstirred water layer (UWL) and receptor sink on the in-vitro transmembrane permeability of an increasingly lipophilic series of compounds (mannitol (MAN), diazepam (DIA) and cinnarizine (CIN) have been assessed. Aletered carbogen bubbling rates were used as a means to change the UWL thickness and polysiorbate-80 (PS-80), biovine serum albumin (BSA) and alpha-1-acid data for MAN, DIA and CIN were consistenet across varying donor PS-80 concentrations suggesting that for the drugs examined here, the donor UWL did not limit in-vitro permeability. Similarly, altered bubbling rates and receptor sink conditions had no impact on the permeability of MAN. In contrast, decreasing the size of the recepto UWL or adding solubilising agents tot he receptor sink resulted in modest enhancements to the permeabilty of the more lipophilic probe DIA. For the most lipophilic compound, CIN, very significant chnages to measured permeabilty (>30 fold) were possible, but were most evident only after cocomitant changes to both the UWL and sink conditions, suggesting that the effectiveness of enhanced sink conditions were dependent on a decrease int he width of the UWL.