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Titolo:
A COMPARISON OF THE COVALENT BINDING OF CLOZAPINE AND OLANZAPINE TO HUMAN NEUTROPHILS IN-VITRO AND IN-VIVO
Autore:
GARDNER I; LEEDER JS; CHIN T; ZAHID N; UETRECHT JP;
Indirizzi:
UNIV TORONTO,FAC PHARM,19 RUSSELL ST TORONTO ON CANADA UNIV TORONTO,FAC PHARM TORONTO ON CANADA UNIV TORONTO,FAC MED TORONTO ON CANADA CHILDRENS MERCY HOSP,DEPT PHARM KANSAS CITY MO 64108
Titolo Testata:
Molecular pharmacology
fascicolo: 6, volume: 53, anno: 1998,
pagine: 999 - 1008
SICI:
0026-895X(1998)53:6<999:ACOTCB>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED AGRANULOCYTOSIS; REACTIVE METABOLITES; HALOTHANE HEPATITIS; GRANULOCYTOPENIA; ANTIBODIES; TOXICITY; PROTEINS; SERUM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
I. Gardner et al., "A COMPARISON OF THE COVALENT BINDING OF CLOZAPINE AND OLANZAPINE TO HUMAN NEUTROPHILS IN-VITRO AND IN-VIVO", Molecular pharmacology, 53(6), 1998, pp. 999-1008

Abstract

Covalent binding of a reactive metabolite of clozapine to neutrophilsor their precursors is thought to play a role in the development of clozapine-induced agranulocytosis. immunoblotting studies with an anti-clozapine antiserum detected covalent binding of clozapine to human neutrophils in vitro when HOCl was used to generate clozapine reactive metabolite (major clozapine adducts of 31, 49, 58, 78, 86, 126, 160, and 204 kDa). In addition, incubating neutrophils with clozapine and H2O2 (major clozapine adducts of 49 and 58 kDa) or clozapine, H2O2, and human myeloperoxidase (major clozapine adducts of 31, 49, 58, and 126 kDa) also resulted in covalent binding of clozapine to the neutrophils. The covalent binding of clozapine to neutrophils was inhibited by extracellular glutathione when HOCl, but not H2O2 was used to generate reactive metabolite. We found that the antiserum against clozapine also recognized olanzapine, an antipsychotic drug that forms a similar reactive metabolite to clozapine but has not been associated with induction of agranulocytosis. Repeating the in vitro experiments with olanzapine revealed that the major olanzapine-modified polypeptides had molecular masses of 96, 130-170, and 218 kDa. Only relatively low levels of 31, 49, and 58 kDa adducts were observed. Clozapine-modified polypeptides also were detected in neutrophils from patients being treated withclozapine. A major 58-kDa clozapine-modified polypeptide was detectedin all patients tested. In contrast, no drug-modified polypeptides were detected in neutrophils from patients taking olanzapine. The differences in covalent binding exhibited by the two compounds and, in particular, the lack of olanzapine binding to human neutrophils in vivo mayhelp to explain the difference in toxicity of these two drugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 06:46:52