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Titolo:
THE ANTICANCER DRUG 5-FLUOROURACIL IS METABOLIZED BY THE ISOLATED-PERFUSED RAT-LIVER AND IN RATS INTO HIGHLY TOXIC FLUOROACETATE
Autore:
ARELLANO M; MALETMARTINO M; MARTINO R; GIRES P;
Indirizzi:
UNIV TOULOUSE 3,LABS IMRCP,BIOMED NMR GRP,118 ROUTE NARBONNE F-31062 TOULOUSE 4 FRANCE UNIV TOULOUSE 3,LABS IMRCP,BIOMED NMR GRP F-31062 TOULOUSE 4 FRANCE RHONE POULENC RORER,CRVA DRUG DISCOVERY DEPT F-94140 ALFORTVILLE FRANCE
Titolo Testata:
British Journal of Cancer
fascicolo: 1, volume: 77, anno: 1998,
pagine: 79 - 86
SICI:
0007-0920(1998)77:1<79:TAD5IM>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
FLUORO-BETA-ALANINE; MAGNETIC-RESONANCE SPECTROSCOPY; SODIUM FLUOROACETATE; CHROMATOGRAPHIC DETERMINATION; COMPOUND 1080; CARDIOTOXICITY; AMINOTRANSFERASE; NEUROTOXICITY; ACID; 5'-DEOXY-5-FLUOROURIDINE;
Keywords:
5-FLUOROURACIL; ALPHA-FLUORO-BETA-ALANINE; F-19 NUCLEAR MAGNETIC RESONANCE; METABOLISM; FLUOROACETATE; ALPHA-FLUORO-BETA-HYDROXYPROPIONIC ACID; ISOLATED PERFUSED RAT LIVER; RAT URINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
43
Recensione:
Indirizzi per estratti:
Citazione:
M. Arellano et al., "THE ANTICANCER DRUG 5-FLUOROURACIL IS METABOLIZED BY THE ISOLATED-PERFUSED RAT-LIVER AND IN RATS INTO HIGHLY TOXIC FLUOROACETATE", British Journal of Cancer, 77(1), 1998, pp. 79-86

Abstract

We report the first demonstration of the biotransformation of the anti-cancer drug 5-fluorouracil (FU) into two new metabolites, alpha-fluoro-beta-hydroxypropionic acid (FHPA) and fluoroacetate (FAG), in the isolated perfused rat liver (IPRL) and in the rat in vivo. IPRL was perfused with solutions of pure FU at two doses, 15 or 45 mg kg(-1) body weight, and rats were injected i.p. with 180 mg of FU kg(-1) body weight. Fluorine-19 NMR analysis of perfusates from IPRL and rat urine showed the presence of the normal metabolites of FU and low amounts of FHPA (0.4% or 0.1% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.08% of the injected FU in rat urine) and FAC (0.1% or 0.03% of injected FU in perfusates from IPRL treated with 15 or 45 mg of FU kg(-1) body weight, respectively; 0.003% of the injected FU in rat urine). IPRL was also perfusedwith a solution of alpha-fluoro-beta-alanine (FBAL) hydrochloride at 16.6 mg kg(-1) body weight dose equivalent to 15 mg of FU kg(-1) body weight. Low amounts of FHPA (0.2% of injected FBAL) and FAC (0.07%) were detected in perfusates, thus demonstrating that FHPA and FAC arise from FBAL catabolism. As FAC is a well-known cardiotoxic poison, and FHPA is also cardiotoxic at high doses, the cardiotoxicity of FU might stem from at least two sources. The first one, established in previouspapers (Lemaire et al, 1992, 1994), is the presence in commercial solutions of FU of degradation products of FU that are metabolized into FHPA and FAG; these are formed over time in the basic medium necessary to dissolve the drug. The second, demonstrated in the present study, is the metabolism of FU itself into the same compounds.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/07/20 alle ore 23:36:40