Dodds H M, Haaz M C, Riou J F, Robert J, Rivory L P
Institut Bergonié, Bordeaux, France.
J Pharmacol Exp Ther. 1998 Jul;286(1):578-83.
Irinotecan, or CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine++ +), is a water-soluble derivative of camptothecine with promising activity against several types of malignancies. In addition to 7-ethyl-10-hydroxycamptothecine (SN-38), its active metabolite, we were able to identify several metabolites in the plasma of patients treated with this drug, especially an oxidative metabolite, 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine. During our study of the biosynthesis of 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine from CPT-11 by human liver microsomes, we were able to detect another quantitatively important polar metabolite, which was also present in the plasma and urine of patients treated with CPT-11. On the basis of preliminary experiments, the structure of this compound was postulated to be 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine, and this structure was synthesized by Rhône-Poulenc Rorer. Urine samples and human liver microsomal extracts were studied by high-performance liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry to identify its structure formally. The identification of the metabolite was supported by identical retention time, mass-to-charge ratio and tandem mass spectrometry fragmentation as a synthetic standard. Like irinotecan, 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecine was a weak inhibitor of cell growth of P388 cells in culture (IC50 = 3.4 micrograms/ml vs. 2.8 micrograms/ml for irinotecan and 0.001 microgram/ml for SN-38). It was also a poor inducer of topoisomerase I-DNA cleavable complexes (100-fold less potent than SN-38). However, unlike 7-ethyl-10[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-camptothecine, this new metabolite could be hydrolyzed to SN-38 by human liver microsomes and purified human liver carboxylesterase, though to a lesser extent than irinotecan. This compound can therefore contribute to the activity and toxicity profile of irinotecan in vivo.
伊立替康，即CPT - 11（7 - 乙基 - 10 - [4 - (1 - 哌啶基)-1 - 哌啶基]羰氧基喜树碱），是喜树碱的一种水溶性衍生物，对多种恶性肿瘤具有显著活性。除了其活性代谢产物7 - 乙基 - 10 - 羟基喜树碱（SN - 38）外，我们还在接受该药物治疗的患者血浆中鉴定出了几种代谢产物，特别是一种氧化代谢产物，7 - 乙基 - 10[4 - N - (5 - 氨基戊酸)-1 - 哌啶基]羰氧基喜树碱。在我们利用人肝微粒体研究从CPT - 11生物合成7 - 乙基 - 10[4 - N - (5 - 氨基戊酸)-1 - 哌啶基]羰氧基喜树碱的过程中，我们检测到了另一种在数量上具有重要意义的极性代谢产物，它也存在于接受CPT - 11治疗的患者的血浆和尿液中。基于初步实验，推测该化合物的结构为7 - 乙基 - 10 - (4 - 氨基 - 1 - 哌啶基)羰氧基喜树碱，罗讷 - 普朗克 - 罗瑞尔公司合成了该结构。通过高效液相色谱/大气压化学电离/串联质谱对尿液样本和人肝微粒体提取物进行研究，以正式鉴定其结构。代谢产物的鉴定得到了与合成标准品相同的保留时间、质荷比和串联质谱碎片的支持。与伊立替康一样，7 - 乙基 - 10 - (4 - 氨基 - 1 - 哌啶基)羰氧基喜树碱在培养中对P388细胞的生长是一种弱抑制剂（IC50 = 3.4微克/毫升，而伊立替康为2.8微克/毫升，SN - 38为0.001微克/毫升）。它也是拓扑异构酶I - DNA可裂解复合物的弱诱导剂（效力比SN - 38低100倍）。然而，与7 - 乙基 - 10[4 - N - (5 - 氨基戊酸)-1 - 哌啶基]羰氧基喜树碱不同，这种新的代谢产物可被人肝微粒体和纯化的人肝羧酸酯酶水解为SN - 38，尽管程度比伊立替康小。因此，该化合物可能对伊立替康在体内的活性和毒性特征有影响。
