Rivory L P, Chatelut E, Canal P, Mathieu-Boué A, Robert J
Université de Bordeaux II, France.
Cancer Res. 1994 Dec 15;54(24):6330-3.
The kinetics of the in vivo interconversion of the carboxylate and lactone forms of the prodrug irinotecan, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin (CPT-11), and its active metabolite SN-38 were studied in five patients using a HPLC method that allows the simultaneous determination of all four compounds and detects any hydrolysis of lactones due to inadequate sample handling and storage. The apparent conversion of CPT-11 lactone to the carboxylate in vivo was rapid with a mean half-life of 9.5 min; the carboxylate became the predominant form of plasma CPT-11 soon after the end of the infusion. The ratio of the area under the plasma concentration-time curves of the lactone to total CPT-11 was 36.8 +/- 3.5% (SD). In contrast, SN-38 was present predominantly as the lactone at all times and with little interpatient variability (lactone/total area under the plasma concentration-time curve ratio, 64.0 +/- 3.4%). This may explain in part the promising activity of CPT-11 because CPT derivatives are active against their target, topoisomerase I, only in their lactone form.
采用一种高效液相色谱法对5例患者体内前体药物伊立替康（7-乙基-10-[4-(1-哌啶基)-1-哌啶基]羰基氧喜树碱，CPT-11）的羧酸盐形式和内酯形式及其活性代谢物SN-38的相互转化动力学进行了研究。该方法可同时测定所有4种化合物，并能检测因样品处理和储存不当导致的内酯水解。CPT-11内酯在体内向羧酸盐的表观转化很快，平均半衰期为9.5分钟；输注结束后不久，羧酸盐就成为血浆中CPT-11的主要形式。内酯与总CPT-11的血浆浓度-时间曲线下面积之比为36.8±3.5%（标准差）。相比之下，SN-38在所有时间均主要以内酯形式存在，患者间差异很小（内酯/血浆浓度-时间曲线下总面积之比为64.0±3.4%）。这可能部分解释了CPT-11良好的活性，因为CPT衍生物仅以其内酯形式对其靶点拓扑异构酶I具有活性。
