Identification of a new metabolite of CPT-11 (irinotecan): pharmacological properties and activation to SN-38.
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.
Dodds
H M
HM
Institut Bergonié, Bordeaux, France.
Haaz
M C
MC
Riou
J F
JF
Robert
J
J
Rivory
L P
LP
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008862:Microsomes, Liver / Q000378:metabolism; D014407:Tumor Cells, Cultured
C113402:7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecine; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin