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Titolo:
DIAZEPAM METABOLISM BY HUMAN LIVER-MICROSOMES IS MEDIATED BY BOTH S-MEPHENYTOIN HYDROXYLASE AND CYP3A ISOFORMS
Autore:
ANDERSSON T; MINERS JO; VERONESE ME; BIRKETT DJ;
Indirizzi:
AB HASSLE S-43183 MOLNDAL SWEDEN FLINDERS MED CTR,DEPT CLIN PHARMACOL BEDFORD PK SA 5042 AUSTRALIA
Titolo Testata:
British journal of clinical pharmacology
fascicolo: 2, volume: 38, anno: 1994,
pagine: 131 - 137
SICI:
0306-5251(1994)38:2<131:DMBHLI>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOCHROME-P-450; OMEPRAZOLE; INHIBITION; INVITRO; 4-HYDROXYLASE; POLYMORPHISM; PURIFICATION; OXIDATION; SLOW;
Keywords:
DIAZEPAM; HUMAN MICROSOMES; KINETICS; CYP ISOFORMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
32
Recensione:
Indirizzi per estratti:
Citazione:
T. Andersson et al., "DIAZEPAM METABOLISM BY HUMAN LIVER-MICROSOMES IS MEDIATED BY BOTH S-MEPHENYTOIN HYDROXYLASE AND CYP3A ISOFORMS", British journal of clinical pharmacology, 38(2), 1994, pp. 131-137

Abstract

1 The primary metabolism of diazepam was studied in human liver microsomes in order to investigate the kinetics and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of the main diazepam metabolites, temazepam and N-desmethyldiazepam. 2 The formation kinetics of both metabolites were atypical and consistent with the occurrence of substrate activation. A sigmoid V-max model equivalent to the Hill equation was used to fit the data. The degree of sigmoidicity was greater for temazepam formation than for N-desmethyldiazepam formation, so that the ratio of desmethyldiazepam:temazepam formation increased as the substrate (diazepam) concentration decreased. 3 alpha-Naphthoflavone activated both reactions but with a greater effect on temazepam formation than on N-desmethyldiazepam formation. In the presence of 25 mu M alpha-naphthoflavone the kinetics for both pathways were approximated by Michaelis-Menten kinetics. 4 Studies with a series of CYPisoform selective inhibitors and with an inhibitory anti-CYP2C antibody indicated that temazepam formation was carried out mainly by CYP3A isoforms, whereas the formation of N-desmethyldiazepam was mediated byboth CYP3A isoforms and S-mephenytoin hydroxylase.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/04/20 alle ore 12:45:55