Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans

Citation
A. Santos et al., Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans, CLIN CANC R, 6(5), 2000, pp. 2012-2020
Citations number
24
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
6
Issue
5
Year of publication
2000
Pages
2012 - 2020
Database
ISI
SICI code
1078-0432(200005)6:5<2012:MOI(BC>2.0.ZU;2-J
Abstract
7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11) , a DNA topoisomerase I inhibitor, undergoes several metabolic pathways to generate conjugated and unconjugated derivatives that could be excreted fro m the body, The objective of this study was to determine the oxidative meta bolites of CPT-11 recovered in human urine samples and to identify cytochro me P450 (CYP) involved in their formation, in addition to the already known metabolites of CPT-11 [SN-38, SN-38-G, 7-ethyl-10-[4-N-(5-aminopentanoic a cid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1- piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized meta bolites from the urine of two children and two adults given CPT-11, M1 and M2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moie ty and on the terminal piperidine ring of CPT-11, M3 had a molecular mass o f 602, but its urine concentration in patients was too low to establish its chemical structure by liquid chromatography/mass spectrometry. In vitro incubations with cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, or CYP3A7 did not produce any detectable metabolites, Only CYP3A4 produced both APC and NPC, resulting from the oxidation of the piperidinylpiperidine side chain of CPT-11 along with metabolite M2. The metabolism of CPT-11 by CYP3A5 was markedly different because neither APC or NPC nor M2 was produc ed, whereas only one new metabolite, M4 (molecular weight, 558), was genera ted by de-ethylation of the CPT moiety. No previous study has reported the presence of the MJ metabolite, Production of APC, NPC, MZ, and M4 was preve nted by ketoconazole, a specific CYP3A inhibitor, The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferenti ally metabolized by CYP3A4. In conclusion, CYP3A plays a major role in the metabolism of CPT-11, with some differences of the metabolic profile exhibi ted by 3A4 and 3A5.