RT Journal Article
SR Electronic
T1 Identification of a New Metabolite of CPT-11 (Irinotecan): Pharmacological Properties and Activation to SN-38
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 578
OP 583
VO 286
IS 1
A1 Helen M. Dodds
A1 Marie-Christine Haaz
A1 Jean-François Riou
A1 Jacques Robert
A1 Laurent P. Rivory
YR 1998
UL http://jpet.aspetjournals.org/content/286/1/578.abstract
AB 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 μg/ml vs. 2.8 μg/ml for irinotecan and 0.001 μg/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. The American Society for Pharmacology and Experimental Therapeutics