Reduced-Resistances Model for Enhanced Drug Permeation via a Solubilizing Receiver Medium: A Mechanistic Study with...

A solubilizing receiver medium has been documented to increase drug flux in vitro, but the mechanisms underlying this effect remain poorly understood. This study investigated these mechanisms and established a mathematical model to describe the increase in apparent permeability. Flow rate experiments were performed to quantify the individual boundary layer and membrane resistances associated with diffusion. The impact of nine solubilizing receiver additives, including surfactants, cyclodextrins, and bovine serum albumin, on the flux of griseofulvin was investigated. The increase in apparent permeability followed the rank-order, though not the magnitude, of the solubility enhancement in the receiver (Spearman's ρ = 0.93, p < 0.001, n = 20). The mechanistic model, termed the reduced-resistances model, demonstrates that a solubilizing receiver reduces diffusional resistance in the membrane and in the receiver-side boundary layer. At high ratios of receiver to donor solubility, a hyperbolic relationship was observed where diffusion through the donor-side boundary layer becomes rate-limiting. Additional drug cocktail permeability studies with antipyrine, phenytoin, and meloxicam confirmed the broader applicability of this model. These findings provide a framework for informed receiver selection in permeability assays and underscore the importance of considering the receiver medium when comparing results across experiments.