Die Aminos�ureausscheidung mit der Galle nach Bromsulphophthalein

Clodi, P. H.; Schnack, Hugo G.; Wewalka, F

doi:10.1007/bf01491364

Cited by 5 publications

(2 citation statements)

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“…In the past, chlorpromazine hydrochloride-associated cholestasis has been attributed to hepatic hypersensitivity reactions (Gutman, 1957; Zelman, 1959;Popper & Schaffner, 1959;Zimmerman, 1963), inhibition of bilirubin secretion (Hargreaves, 1965), alteration of bile viscosity (Sharma & Prasad, 1967), precipitation of biliaryproteins (Clarke & Denborough, 1971) and spasm of the sphincter of Oddi (Moyer et al, 1954;Menguy et al, 1955), all without convincing pathophysiological proof. Although there is some direct experimental evidence that inhibition of bile flow both in dogs (Stefko & Zbinden, 1963;Sharma & Prasad, 1967) and in perfused rat liver preparations (Clodi & Schnack, 1960;Kendler et al, 1971) occurs with chlorpromazine hydrochloride and is related to dose, no physicochemical studies have been carried out on the interactions of the drug with bile salts, the major organic anions in mammalian bile, and the substances responsible for much of bile-water flow (Wheeler, 1969;Erlinger, 1972). At physiological pH one would expect that bile salts (Plate 1), which are anionic detergent-like molecules (Carey & Small, 1972), and chlorpromazine hydrochloride (Plate 1), which is acationicdetergent (Scholtan, 1955; Attwood et al, 1974), would be incompatible in solution owing to coulombic interactions between their ionic groups.…”

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confidence: 99%

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

Carey¹,

Hirom²,

Small³

1976

Biochemical Journal

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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.

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