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
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.