A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure

Abstract

Since chlorpromazine hydrochloride [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride] is commonly implicated in causing bile-secretory failure in man and is secreted into bile, we have studied the physicochemical interactions of the drug with the major components of bile in vitro. Chlorpromazine hydrochloride molecules are amphiphilic by virtue of possessing a polar tertiary amine group linked by a short paraffin chain to a tricyclic hydrophobic part. At pH values below the apparent pK (pK'a 7.4) the molecules are water-soluble cationic detergents. We show that bile salts in concentrations above their critical micellar concentrations are precipitated from solution by chlorpromazine hydrochloride as insoluble 1:1 salt complexes. In the case of mixed bile-salt/phosphatidylcholine micellar solutions, however, the degree of precipitation is inhibited by the phospholipid in proportion to its mole fraction. With increases in the concentration of chlorpromazine hydrochloride or bile salt, micellar solubilization of the precipitated complexes results. Sonicated dispersions of the negatively charged phospholipid phosphatidylserine were also precipitated, but dispersions of the zwitterionic phospholipid phosphatidylcholine were not. Chlorpromazine hydrochloride efficiently solubilized these membrane phospholipids as mixed micellar solutions when the drug:phospholipid molar ratio reached 4:1. Polarizing-microscopy and X-ray-diffraction studies revealed that the precipitated complexes were amorphous and potentiometric studies confirmed the presence of a salt bond. Some dissociation of the complex occurred in the case of the most polar bile salt (Ks 0.365). As canalicular bile-salt secretion determines much of bile-water flow, we propose that complexing and precipitation of bile salts by chlorpromazine hydrochloride and its metabolites may be physicochemically related to the reversible bile-secretory failure produced by this drug.

Assessment of solubilization characteristics of different surfactants for carvedilol phosphate as a function of pH

“…Such cases may occur where the release of STC is below cmc where micellar solubilization of the complex formed is not possible. Similar incidence of bile secretory failure because of interaction of drug and STC has been reported for chlorpromazine hydrochloride [34].…”

Relationship between Surface Activity and Toxicity to Chang Liver Cultures of Tricyclic Antidepressants

“…Others have postulated that the detergent prop erties of chlorpromazine may play a role in its cholestatic effects in man (3). We have previ ously demonstrated a positive correlation be tween hepatotoxic potential in vitro and sur face activity for erythromycin derivatives (8), phenothiazines (10) and bile acids (9).…”

Chlorpromazine, Administered in Vivo and in Vitro, Inhibits the Efflux of Bile Acids in Freshly Isolated Rat Hepatocytes*

“…Several additional mechanisms should be considered which might relate to the effect of chlorpromazine on bile acid efflux. First, there is evidence that chlorpromazine interacts electrostatically with bile acids and that these electrostatic complexes precipitate from solution (Carey et al 1976). This precipitation may occur either within the hepatocyte or in the biliary canaliculus.…”