IDENTIFICATION AND PROPERTIES OF A MAJOR PLASMA METABOLITE OF IRINOTECAN (CPT-11) ISOLATED FROM THE PLASMA OF PATIENTS

Citation
Lp. Rivory et al., IDENTIFICATION AND PROPERTIES OF A MAJOR PLASMA METABOLITE OF IRINOTECAN (CPT-11) ISOLATED FROM THE PLASMA OF PATIENTS, Cancer research, 56(16), 1996, pp. 3689-3694
Citations number
19
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
56
Issue
16
Year of publication
1996
Pages
3689 - 3694
Database
ISI
SICI code
0008-5472(1996)56:16<3689:IAPOAM>2.0.ZU;2-3
Abstract
Irinotecan 1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) ] is a promising water-soluble analogue of camptothecin [S. Sawada et at, Chem. & Pharm, Bull, (Tokyo), 39: 1446-1454, 1991], We have report ed previously the presence of an important polar metabolite, in additi on to 7-ethyl-10-hydroxycamptothecin (SN-38) beta-glucuronide, in samp les of plasma taken from patients undergoing treatment with CPT-11 (L. P. Rivory and J, Robert, Cancer Chemother. Pharmacol, 36: 176-179, 19 95; L. P. Rivory and J, Robert, J, Cromatogr, 661: 133-141, 1994), Pla sma samples (0.5 ml) containing comparatively large amounts of this me tabolite were extracted by solid-phase columns and subjected to highpe rformance liquid chromatography and mass spectrometry in parallel to f luorometric detection. The metabolite yielded [M+1] ions with a m/z of 619, representing the addition of 32 atomic mass units to CPT-11, Pur ified fractions were subjected to proton nuclear magnetic resonance, a nd the structure determined, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1 -piperidino]carbonyloxycamptothecin (APC), was further validated follo wing 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 verses 5.5 mu g/m l for CPT-11 and 0.01 mu g/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 C PT-II in these preparations, Interestingly, APC was only a weak inhibi tor of acetylcholinesterase in comparison to CPT-11 and neostigmine. I t appears likely, therefore, that APC does not contribute directly to the activity and toxicity profile of CPT-11 in vivo.