Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
Bioactivation and covalent binding of hydroxyfluperlapine in human neutrophils: Implications for fluperlapine-induced agranulocytosis
Autore:
Lai, WG; Gardner, I; Zahid, N; Uetrecht, JP;
Indirizzi:
Univ Toronto, Fac Pharm, Toronto, ON M5S 2S2, Canada Univ Toronto TorontoON Canada M5S 2S2 Pharm, Toronto, ON M5S 2S2, Canada Univ Toronto, Fac Med, Toronto, ON M5S 2S2, Canada Univ Toronto Toronto ON Canada M5S 2S2 c Med, Toronto, ON M5S 2S2, Canada
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 3, volume: 28, anno: 2000,
pagine: 255 - 263
SICI:
0090-9556(200003)28:3<255:BACBOH>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
CLOZAPINE-INDUCED AGRANULOCYTOSIS; REACTIVE METABOLITES; IN-VITRO; AMODIAQUINE; LEUKOCYTES; OXIDATION; OLANZAPINE; TOXICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Uetrecht, JP Univ Toronto, Fac Pharm, 19 Russell St, Toronto, ON M5S 2S2, Canada Univ Toronto 19 Russell St Toronto ON Canada M5S 2S2 , Canada
Citazione:
W.G. Lai et al., "Bioactivation and covalent binding of hydroxyfluperlapine in human neutrophils: Implications for fluperlapine-induced agranulocytosis", DRUG META D, 28(3), 2000, pp. 255-263

Abstract

The use of fluperlapine and the structurally related clozapine has been associated with the induction of agranulocytosis in humans. Unlike clozapine,fluperlapine is relatively resistant to chemical and biochemical oxidations. In this study we demonstrated that 7-hydroxyfluperlapine, the major metabolite of fluperlapine in humans, is oxidized to a reactive intermediate byHOCl and by myeloperoxidase in the presence of H2O2 and Cl-. This reactiveintermediate was identified as an iminoquinone species with a M + 1 ion atm/z 324 by mass spectrometry. The iminoquinone intermediate was trapped byN-acetyl-L-cysteine (NAC) as well as GSH. NMR spectra of the NAC adducts indicated that the NAC was bound to the 6 and 9 positions of the aromatic ring. This is the same orientation as the binding of nucleophiles to the reactive metabolite of clozapine. We were able to use an antibody against clozapine to demonstrate that 7-hydroxyfluperlapine, but not fluperlapine itself, covalently modifies human myeloperoxidase. Furthermore, we demonstrated that 7-hydroxyfluperlapine is metabolized by activated neutrophils to a reactive intermediate that covalently binds to neutrophils. In the presence of NAC or GSH, such covalent binding was inhibited and the NAC or GSH adducts were formed. Thus, the reactivity and even the orientation of the binding of the reactive metabolite of 7-hydroxyfluperlapine is very similar to that of clozapine. These results provide a mechanism for the formation of a reactive metabolite of fluperlapine similar to clozapine that may explain its ability to induce agranulocytosis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 24/01/20 alle ore 12:18:43