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[Cancer Research 56, 3689-3694, August 15, 1996]
© 1996 American Association for Cancer Research
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Identification and Properties of a Major Plasma Metabolite of Irinotecan (CPT-11) Isolated from the Plasma of Patients1

Laurent P. Rivory2, Jean-François Riou, Marie-Christine Haaz, Serge Sable, Marc Vuilhorgne, Alain Commerçon, Susan M. Pond and Jacques Robert

University of Queensland, Department of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia [L. P. R., S. M. P.]; Rhône Poulenc Rorer SA. Research and Development, Vitry sur Seine Cedex 94403 [J-F. R., S. S., M. V., A. C.]; Institut Bergonié, Bordeaux Cedex 33076 [L. P. R., J. R.]; and Université de Bordeaux II, 146 rue Léo Saignat, Bordeaux 33000 [M-C. H., J. R.], France

Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino)carbonyloxycamptothecin (CPT-11)] is a promising water-soluble analogue of camptothecin [S. Sawada et al., Chem. & Pharm. Bull. (Tokyo), 39: 1446–1454, 1991]. We have reported previously the presence of an important polar metabolite, in addition to 7-ethyl-10-hydroxycamptothecin (SN-38) ß-glucuronide, in samples of plasma taken from patients undergoing treatment with CPT-11 (L. P. Rivory and J. Robert, Cancer Chemother. Pharmacol. 36: 176–179, 1995; L. P. Rivory and J. Robert, J. Cromatogr., 661: 133–141, 1994). Plasma samples (0.5 ml) containing comparatively large amounts of this metabolite were extracted by solid-phase columns and subjected to high-performance liquid chromatography and mass spectrometry in parallel to fluorometric detection. The metabolite yielded [M+1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11. Purified fractions were subjected to proton nuclear magnetic resonance, and the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC), was further validated following synthesis. Like CPT-11, APC was found to be only a weak inhibitor of the cell growth of KB cells in culture (IC50, 2.1 versus 5.5 µg/ml for CPT-11 and 0.01 µg/ml for SN-38, the active metabolite of CPT-11) and was a poor inducer of topoisomerase I DNA-cleavable complexes (100-fold less potent than SN-38). In contrast to CPT-11, APC was not hydrolyzed to SN-38 by human liver microsomes or purified human liver carboxylesterase. Furthermore, APC did not inhibit the hydrolysis of CPT-11 in these preparations. Interestingly, APC was only a weak inhibitor of acetylcholinesterase in comparison to CPT-11 and neostigmine. It appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo.

1 This work was supported in part by Australian National Health and Medical Research Council Grant 920298 and the Association pour la Recherche contre le Cancer (France). L. P. R. is the recipient of a National Health and Medical Research Council-Institut National de la Santé et de la Recherche Médicale Exchange Fellowship. Presented in part at the 87th Annual Meeting of the American Association for Cancer Research, Inc., April 20–24, 1996, Washington, DC.

2 To whom requests for reprints should be addressed, at Department of Medicine, University of Queensland, Princess Alexandra Hospital, Ipswich Rd., Woolloongabba, Queensland 4102, Australia.

Received 2/21/96. Accepted 6/18/96.




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