Quantitative estimation of drug permeation through nasal mucosa using in vitro membrane permeability across Calu-3 cell layers for predicting in vivo bioavailability after intranasal administration to rats.

For establishing a precise system for predicting in vivo bioavailability following intranasal (IN) administration, the relationships among membrane permeability of drugs across Calu-3 cells, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration were quantified. The membrane permeability coefficient (Papp) was determined for sixteen model drugs by in vitro permeation studies in Calu-3 cells. The drug permeation rate constant through the nasal mucosa (kn) was calculated from the in situ nasal perfusion of the drug solutions in rats. Bioavailability following IN administration of six model drugs with different membrane permeabilities were determined by in vivo drug absorption studies in rats. The correlations among in vitro membrane permeability properties, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration, were assessed. The significant correlation between the in vitro Calu-3 cell permeability and nasal mucosal drug permeation rate (r2=0.812, p<0.001) indicated that nasal mucosal drug permeability is estimable from in vitro membrane permeability. Furthermore, bioavailability following IN administration significantly correlated with the in vitro Papp across Calu-3 cells (r2=0.984, p<0.001), suggesting that in vivo drug absorption following IN administration can be predicted from in vitro Calu-3 membrane permeability.