Physicochemical and biological characterization of monoketocholic acid, a novel permeability enhancer

Bile salts are endogenous surfactants which have been widely used in drug formulation and drug delivery systems to increase drug permeation. When given by subcutaneous injection to rats, the novel bile salt, monoketocholate (MKC) has been shown to increase brain uptake of several drugs. This study aimed to characterize the physicochemical and some biological properties of MKC as a basis for understanding the mechanism by which it enhances membrane permeability. Comparison was made with three natural bile salts, cholate, deoxycholate and taurocholate. Critical micelle concentrations (CMC) were measured by the surface tension method and partition coefficients in n-octanol/buffer were measured by liquid-liquid extraction. The effects of bile salts on three different biological membrane models were investigated. Penetration studies in Langmuir monolayers indicated that MKC has only a weak ability to insert into phospholipid monolayers, but it can increase their elasticity once incorporated. In the erythrocyte model, MKC did not cause hemolysis at concentrations up to 10 mM, but changed the deformability of erythrocytes. Studies of the permeability of mannitol and transepithelial electrical resistance (TEER) across Caco-2 cell monolayers showed MKC did not cause significant increases in mannitol permeability or decreases in TEER values. In conclusion, MKC does not display strong membrane-solubilizing properties, but does change the mechanical properties of biological membranes. This effect might influence both passive and active transcellular permeation.