CHRISTUS Stehlin Foundation for Cancer Research, 10301 Stella Link Road, Houston, Texas 77025, USA.
J Pharm Pharm Sci. 2013;16(1):115-24. doi: 10.18433/j3b604.
The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice.
In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations.
The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules.
The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood.
本研究旨在探讨新型抗癌药物 CZ48（喜树碱的 C20-丙酸酯）在小鼠体内的药代动力学行为与毒性之间的关系。
在本研究中，我们比较了 CZ48 口服剂量的安全性和药代动力学特性与喜树碱（CPT）口服剂量的差异。将三种不同剂量的 CZ48（50、200 和 1000mg/kg）和两种不同剂量的 CPT（1.5mg/kg 和 6.0mg/kg）中的一种分别给予小鼠口服。在给药后规定的时间点从所有小鼠中采集血样，以评估血浆 CZ48 和 CPT 浓度。
研究表明，CZ48 在小鼠血液中非常稳定，当在循环中时，其大部分以内酯形式保持完整，只有一小部分 CZ48 分子代谢为 CPT。在小鼠血液中测量到的代谢物 CPT 的浓度仅为普通 CPT 最大耐受剂量（6.0mg/kg）的 3%。这两种分子在血液中的稳定性差异可以从它们的结构上得到解释。
在有效剂量下，CZ48 在小鼠中没有毒性，这归因于其在血液中的稳定性增强。
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