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Titolo:
N-HYDROXYLATION OF DAPSONE BY MULTIPLE ENZYMES OF CYTOCHROME-P450 - IMPLICATIONS FOR INHIBITION OF HAEMOTOXICITY
Autore:
GILL HJ; TINGLE MD; PARK BK;
Indirizzi:
UNIV LIVERPOOL,DEPT THERAPEUT & PHARMACOL,POB 147 LIVERPOOL L69 3BX MERSEYSIDE ENGLAND UNIV LIVERPOOL,DEPT THERAPEUT & PHARMACOL LIVERPOOL L69 3BX MERSEYSIDE ENGLAND
Titolo Testata:
British journal of clinical pharmacology
fascicolo: 6, volume: 40, anno: 1995,
pagine: 531 - 538
SICI:
0306-5251(1995)40:6<531:NODBME>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
TRIMETHOPRIM-SULFAMETHOXAZOLE; ADVERSE REACTIONS; INFECTED PATIENTS; CIMETIDINE; DERIVATIVES; METABOLISM; MICROSOMES; DEFICIENCY;
Keywords:
DAPSONE; HYDROXYLAMINE; METABOLISM; INHIBITION; CYTOCHROME P450; TOXICITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
45
Recensione:
Indirizzi per estratti:
Citazione:
H.J. Gill et al., "N-HYDROXYLATION OF DAPSONE BY MULTIPLE ENZYMES OF CYTOCHROME-P450 - IMPLICATIONS FOR INHIBITION OF HAEMOTOXICITY", British journal of clinical pharmacology, 40(6), 1995, pp. 531-538

Abstract

1 The adverse reactions associated with the administration of dapsoneare believed to be caused by metabolism to its hydroxylamine. Previous reports suggest that CYP3A4 is responsible for this biotransformation [1]. 2 Data presented in this paper illustrate the involvement of more than one cytochrome P450 enzyme in dapsone hydroxylamine formation using human liver microsomes. Eadie-Hofstee plots demonstrated bi-phasic kinetics in several livers. No correlation could be established between hydroxylamine formation and CYP3A concentrations in six human livers (r = -0.47; P = 0.34). 3 Studies with low molecular weight inhibitors illustrate the importance of CYP2C9 and CYP3A in dapsone N-hydroxylation. 4 Differential sensitivity of dapsone N-hydroxylation to selective CYP inhibitors indicated that the contribution of individual CYP enzymes varies between livers. Selective inhibition ranged from 6.8 to44.4% by 5 mu M ketoconazole, and from 24.0 to 68.4% by 100 mu M sulphaphenazole. The extent of inhibition, by either ketoconazole or sulphaphenazole was dependent on the CYP3A content of the liver. 5 The levels of expression of these cytochrome P450 enzymes may be an important determinant of individual susceptibility to the toxic effects of dapsone, and may influence the ability of an enzyme inhibitor to block dapsone toxicity in vivo. Because of the inability to produce complete inhibition, selective CYP inhibitors are unlikely to offer any clinical advantage over cimetidine in decreasing dapsone hydroxylamine formationin vivo.

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Documento generato il 07/07/20 alle ore 15:41:50