Toxicity of promazine and chlorpromazine to isolated rat hepatocytes and its modification by liposome entrapment.

Isolated rat hepatocytes were used to determine the relationship between magnitude of uptake by cells and cytotoxic effects of chlorpromazine (CPZ) and promazine (PZ). Cell injury was evaluated by the extent of leakage of cytoplasmic and lysosomal enzymes from cells to surrounding medium and by cytopathic changes seen under surface scanning electron microscopy, after drug exposure. The drug uptake was time- and dose-dependent; cell preparations exposed to equal concentrations of either drug in the medium contained a twice greater concentration of CPZ than of PZ. Cytoplasmic and lysosomal enzyme leakage from cells exposed to 200 and 500 microM of CPZ showed significantly greater toxicity than control cells or those exposed to PZ at the same concentration. Surface activity of drugs was determined to calculate their surface excess. The surface pressure of CPZ is about twice that of PZ at equimolar concentration and correlated with extent of drug uptake and toxicity, suggesting that the surfactibility could play a role in bioavailability and toxicity of these drugs to liver cell membranes. Cytotoxicity was decreased by entrapment of CPZ inside liposomes; up to 40% for lactate dehydrogenase leakage and 47% of beta-glucuronidase, presenting further evidence for the potential use of liposomes.