PT  - JOURNAL ARTICLE
AU  - Rivory, Laurent P.
AU  - Riou, Jean-François
AU  - Haaz, Marie-Christine
AU  - Sable, Serge
AU  - Vuilhorgne, Marc
AU  - Commerçon, Alain
AU  - Pond, Susan M.
AU  - Robert, Jacques
TI  - Identification and Properties of a Major Plasma Metabolite of Irinotecan (CPT-11) Isolated from the Plasma of Patients
DP  - 1996 Aug 15
TA  - Cancer Research
PG  - 3689--3694
VI  - 56
IP  - 16
4099  - http://cancerres.aacrjournals.org/content/56/16/3689.short
4100  - http://cancerres.aacrjournals.org/content/56/16/3689.full
SO  - Cancer Res1996 Aug 15; 56
AB  - 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) β-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. ©1996 American Association for Cancer Research.