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Titolo:
Mass spectrometric and NMR characterization of metabolites of roxifiban, apotent and selective antagonist of the platelet glycoprotein IIb/IIIa receptor
Autore:
Mutlib, AE; Diamond, S; Shockcor, J; Way, R; Nemeth, G; Gan, L; Christ, DD;
Indirizzi:
Dupont Co, Stine Haskell Res Ctr, Drug Metab & Pharmacokinet Sect, Newark,DE 19714 USA Dupont Co Newark DE USA 19714 b & Pharmacokinet Sect, Newark,DE 19714 USA Dupont Co, Stine Haskell Res Ctr, Dept Chem & Phys Sci, Newark, DE 19714 USA Dupont Co Newark DE USA 19714 Dept Chem & Phys Sci, Newark, DE 19714 USA
Titolo Testata:
XENOBIOTICA
fascicolo: 11, volume: 30, anno: 2000,
pagine: 1091 - 1110
SICI:
0049-8254(200011)30:11<1091:MSANCO>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTICONVULSANT AGENT ZONISAMIDE; HPLC-NMR; IN-VITRO; IDENTIFICATION; SPECTROSCOPY; RESOLUTION; EXCRETION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
14
Recensione:
Indirizzi per estratti:
Indirizzo: Mutlib, AE Dupont Co, Stine Haskell Res Ctr, Drug Metab & Pharmacokinet Sect, POB 30,Elkton Rd, Newark, DE 19714 USA Dupont Co POB 30,Elkton Rd Newark DE USA 19714 rk, DE 19714 USA
Citazione:
A.E. Mutlib et al., "Mass spectrometric and NMR characterization of metabolites of roxifiban, apotent and selective antagonist of the platelet glycoprotein IIb/IIIa receptor", XENOBIOTICA, 30(11), 2000, pp. 1091-1110

Abstract

1. The methyl ester prodrug roxifiban is an orally active, potent and selective antagonist of the platelet glycoprotein GPIIb/IIIa receptor and is being del eloped for the prevention and treatment of arterial thrombosis.2. Roxifiban was rapidly hydrolyzed to the zwitterion XV459 in vivo and byliver slices from the rat, mouse and human and by intestinal cores from dog. XV459 was metabolized to only a small extent in vitro and in vivo.3. Studies with rat and dog given radiolabelled roxifiban showed limited oral absorption with the majority of the radiolabel being excreted ill faeces. After i.v. doses of C-14- roxifiban, most of the radioactivity was recovered in the urine of rat whereas the dog excreted significant amounts of radioactivity in bile and urine.4. XV459 could be metabolized extrahepatically by dog gut flora to producean isoxazoline ring-opened metabolite. In vitro hepatic metabolism of XV459 was mainly by hydroxylation at the prochiral and chiral centres of the isoxazoline ring. These hydroxylated metabolites were not detected in the urine and plasma of human volunteers administered roxifiban.5. Initial LC/MS identification of metabolites was achieved by dosing the rat with an equimolar mixture of d(o):d(4) roxifiban and detecting isotopicclusters of pseudomolecular ions. Unequivocal characterization of these metabolites was achieved by LC/MS, LC/NMR and high-field NMR techniques usingsynthetic standards of the metabolites.6. The synthesis of one hydroxylated metabolite enabled the assignment of the correct stereochemistry of the substituted hydroxyl group on the isoxazoline ring.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/07/20 alle ore 07:23:58