Effects of bile salts on propranolol distribution into liposomes studied by capillary electrophoresis

Abstract

The objective of this study was to study the effect of four different bile salts, cholate (C), deoxycholate (DC), taurocholate (TC), monoketocholate (MKC), on the membrane binding of a cationic model drug, propranolol, using capillary electrophoresis. The apparent distribution coefficient of propranolol in a buffer/liposome system, in the absence and presence of various concentrations of the bile salts, was measured using capillary electrophoresis frontal analysis. At bile salt concentrations which did not disrupt the liposomes, the bile salts increased the apparent distribution coefficient of propranolol in a concentration-dependent manner, to various extents (DC>C>TC>MKC). The mechanisms for these increases were inferred from studies of ion pairing between bile salts and propranolol using mobility shift affinity capillary electrophoresis and from zeta potential measurements. The bile salts ion-paired with propranolol to different extents as indicated by the estimated complexation constants (K range: 30-58 M(-1)). This was found to have a minor effect on the membrane distribution of propranolol only. The major effect is proposed to be due to the insertion of bile salt into the liposomal membranes leading to a more negatively charged membrane surface thereby providing stronger electrostatic interactions with the positively charged propranolol.