Salhab A S, Dujovne C A
Pharmacology. 1986;33(6):311-21. doi: 10.1159/000138232.
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.
采用分离的大鼠肝细胞来确定细胞摄取量与氯丙嗪（CPZ）和丙嗪（PZ）细胞毒性作用之间的关系。在药物暴露后，通过细胞质和溶酶体酶从细胞泄漏到周围培养基中的程度以及表面扫描电子显微镜下观察到的细胞病变变化来评估细胞损伤。药物摄取具有时间和剂量依赖性；在培养基中暴露于相同浓度的两种药物的细胞制剂中，CPZ的浓度比PZ高两倍。暴露于200和500微摩尔CPZ的细胞中，细胞质和溶酶体酶泄漏显示出比对照细胞或暴露于相同浓度PZ的细胞明显更大的毒性。测定药物的表面活性以计算其表面过剩量。在等摩尔浓度下，CPZ的表面压力约为PZ的两倍，且与药物摄取程度和毒性相关，这表明表面活性可能在这些药物对肝细胞膜的生物利用度和毒性中起作用。将CPZ包裹在脂质体内可降低细胞毒性；乳酸脱氢酶泄漏降低高达40%，β-葡萄糖醛酸酶降低47%，这为脂质体的潜在用途提供了进一步的证据。
