Scott D O, Bindra D S, Stella V J
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence 66044.
Pharm Res. 1993 Oct;10(10):1451-7. doi: 10.1023/a:1018919224450.
20(S)-Camptothecin exists in equilibrium between its lactone (CPT) and its carboxylate forms (Na-CPT) under stimulated physiological conditions, with the equilibrium favoring the carboxylate form. The rates of lactone hydrolysis were studied in plasma, serum albumin, and blood and were found to be faster than in aqueous buffers at equivalent pH values. From mechanistic information and in vivo activity data, the lactone appears to be the active form of the drug. It has been argued, therefore, that if an equilibrium existed between the lactone and the carboxylate, Na-CPT could be used to deliver the lactone effectively. In the present study, plasma pharmacokinetics were performed in sodium pentobarbital-anesthetized rats treated with both CPT (lactone) and the sodium salt of camptothecin (carboxylate, Na-CPT) and the lactone and carboxylate, as well as the total drug, concentration versus time profiles were assessed. It was found that plasma concentrations and AUC values for the lactone were significantly higher after dosing with CPT than after dosing with Na-CPT. After i.v. administration, the ratio of plasma lactone to carboxylate was skewed by the apparent rapid and extensive uptake of the lactone into tissues and the rapid clearance of both species. From our results, it appears that the lower in vivo activity of Na-CPT compared to that from CPT administration might be attributed to the altered conversion of carboxylate into lactone in vivo compared to that predicted from in vitro data.
在刺激的生理条件下，20(S)-喜树碱在其内酯形式（CPT）和羧酸盐形式（Na-CPT）之间存在平衡，且该平衡有利于羧酸盐形式。研究了内酯在血浆、血清白蛋白和血液中的水解速率，发现其水解速率比在相同pH值的水性缓冲液中更快。从机理信息和体内活性数据来看，内酯似乎是药物的活性形式。因此，有人认为，如果内酯和羧酸盐之间存在平衡，Na-CPT可有效地递送内酯。在本研究中，对用CPT（内酯）和喜树碱钠盐（羧酸盐，Na-CPT）处理的戊巴比妥钠麻醉大鼠进行了血浆药代动力学研究，并评估了内酯、羧酸盐以及总药物的浓度-时间曲线。结果发现，给予CPT后内酯的血浆浓度和AUC值显著高于给予Na-CPT后。静脉注射后，内酯向组织中的明显快速且广泛摄取以及两种形式的快速清除导致血浆内酯与羧酸盐的比例发生偏差。从我们的结果来看，与给予CPT相比，Na-CPT较低的体内活性可能归因于与体外数据预测相比，体内羧酸盐向内酯的转化发生了改变。
