Kaneda N, Hosokawa Y, Yokokura T, Awazu S
Yakult Central Institute for Microbiological Research, Tokyo, Japan.
Biol Pharm Bull. 1997 Sep;20(9):992-6. doi: 10.1248/bpb.20.992.
We studied the plasma pharmacokinetics of the lactone form and the carboxylate form of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan (CPT-11), after intravenous bolus administrations of each form of SN-38 and of CPT-11 to rats. After the SN-38 lactone injection, SN-38 lactone was predominant at first, and then the lactone to the carboxylate concentration ratio (LC ratio) was maintained from 30 to 90 min after the injection. The carboxylate was predominant throughout the period after the carboxylate dosing. Model-dependent analyses showed that the SN-38 lactone had greater plasma clearance and a greater distribution volume than the carboxylate. The CPT-11 administration resulted in a predominant plasma SN-38 lactone concentration. The contribution of the SN-38 lactone AUC to the total SN-38 AUC (57%) was independent of the dose of CPT-11. These results suggest that it is possible to estimate the SN-38 lactone concentration and AUC from the total SN-38 concentration without separate determination of the lactone and carboxylate. Our results showed that both SN-38 lactone and CPT-11 administration gave the predominant SN-38 lactone in plasma; however, only CPT-11 could sustain the lactone concentration at a high level, which is necessary for antitumor activity.
我们研究了伊立替康（CPT-11）的活性代谢产物7-乙基-10-羟基喜树碱（SN-38）的内酯形式和羧酸盐形式在静脉推注每种形式的SN-38和CPT-11给大鼠后血浆中的药代动力学。注射SN-38内酯后，起初SN-38内酯占主导，然后内酯与羧酸盐浓度比（LC比）在注射后30至90分钟保持稳定。羧酸盐给药后的整个时间段内羧酸盐占主导。基于模型的分析表明，SN-38内酯比羧酸盐具有更大的血浆清除率和更大的分布容积。CPT-11给药导致血浆中SN-38内酯浓度占主导。SN-38内酯AUC对总SN-38 AUC的贡献（57%）与CPT-11的剂量无关。这些结果表明，无需分别测定内酯和羧酸盐，就有可能从总SN-38浓度估算SN-38内酯浓度和AUC。我们的结果表明，SN-38内酯和CPT-11给药后血浆中均以SN-38内酯占主导；然而，只有CPT-11能将内酯浓度维持在高水平，这是抗肿瘤活性所必需的。
