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Titolo:
Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans
Autore:
Santos, A; Zanetta, S; Cresteil, T; Deroussent, A; Pein, F; Raymond, E; Vernillet, L; Risse, ML; Boige, V; Gouyette, A; Vassal, G;
Indirizzi:
Inst Gustave Roussy, UMR 8532,CNRS, Dept Pharmacotoxicol & Pharmacogenet, F-94805 Villejuif, France Inst Gustave Roussy Villejuif France F-94805 , F-94805 Villejuif, France Inst Gustave Roussy, Dept Med Oncol, F-94805 Villejuif, France Inst Gustave Roussy Villejuif France F-94805 , F-94805 Villejuif, France Inst Gustave Roussy, Dept Pediat Oncol, F-94805 Villejuif, France Inst Gustave Roussy Villejuif France F-94805 , F-94805 Villejuif, France Ctr Leon Berard, Dept Med Oncol, F-69008 Lyon, France Ctr Leon Berard Lyon France F-69008 Dept Med Oncol, F-69008 Lyon, France Rhone Poulenc Rorer SA, F-92160 Antony, France Rhone Poulenc Rorer SA Antony France F-92160 SA, F-92160 Antony, France Bellon, F-92120 Montrouge, France Bellon Montrouge France F-92120Bellon, F-92120 Montrouge, France
Titolo Testata:
CLINICAL CANCER RESEARCH
fascicolo: 5, volume: 6, anno: 2000,
pagine: 2012 - 2020
SICI:
1078-0432(200005)6:5<2012:MOI(BC>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
DNA-TOPOISOMERASE-I; HUMAN-LIVER; THERAPEUTIC ACTIVITY; SN-38; IDENTIFICATION; NEUROBLASTOMA; DERIVATIVES; MICROSOMES; EXPRESSION; XENOGRAFTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Vassal, G Inst Gustave Roussy, UMR 8532,CNRS, Dept Pharmacotoxicol & Pharmacogenet, 39 Rue Camille Desmoulins, F-94805 Villejuif, France Inst GustaveRoussy 39 Rue Camille Desmoulins Villejuif France F-94805
Citazione:
A. Santos et al., "Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans", CLIN CANC R, 6(5), 2000, pp. 2012-2020

Abstract

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11), a DNA topoisomerase I inhibitor, undergoes several metabolic pathways togenerate conjugated and unconjugated derivatives that could be excreted from the body, The objective of this study was to determine the oxidative metabolites of CPT-11 recovered in human urine samples and to identify cytochrome 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 acid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized metabolites from the urine of two children and two adults given CPT-11, M1 andM2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moiety and on the terminal piperidine ring of CPT-11, M3 had a molecular mass of 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 producedboth 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 produced, whereas only one new metabolite, M4 (molecular weight, 558), was generated by de-ethylation of the CPT moiety. No previous study has reported thepresence of the MJ metabolite, Production of APC, NPC, MZ, and M4 was prevented by ketoconazole, a specific CYP3A inhibitor, The parameters of CPT-11biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4. In conclusion, CYP3A plays a major role in themetabolism of CPT-11, with some differences of the metabolic profile exhibited by 3A4 and 3A5.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/11/20 alle ore 04:47:23