Incorporation of chlorpromazine into bilayer liposomes for protection against microsomal metabolism and liver absorption.

Chlorpromazine (CPZ) was incorporated into bilayer liposomes carrying negative charges either from phosphatidic acid (PA) or from phosphatidyl inositol (PI). CPZ incorporation was dependent on the amount of negatively charged lipid present in the liposomes. At a concentration of 0.6 mol parts phosphatidic acid as referred to egg phosphatidyl choline (EPC) as matrix lipid, 80 micrograms CPZ/mg EPC were stably incorporated. At the saturation concentration a 1:1 molar complex between the phenothiazine drug and the negatively charged lipid is formed. This lipophilic complex retains the CPZ molecules firmly within the lipid bilayer. In vitro release of CPZ into the medium surrounding the liposomes was found to be a very slow process with release half-times of 30 to 99 hours depending on liposome composition. Microsomal metabolism of liposomally incorporated CPZ was slowed and reduced by 50% as determined by the formation of CPZ-sulfoxide. In single pass liver perfusion experiments it was shown that CPZ absorption is significantly reduced when CPZ is incorporated into liposomes. It is suggested that this protective effect of the liposomes might influence the pharmacological effects of CPZ and reduce its hepatotoxic properties.