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Titolo:
IDENTIFICATION OF HUMAN LIVER CYTOCHROME-P450 ISOFORMS MEDIATING OMEPRAZOLE METABOLISM
Autore:
ANDERSSON T; MINERS JO; VERONESE ME; TASSANEEYAKUL W; TASSANEEYAKUL W; MEYER UA; BIRKETT DJ;
Indirizzi:
ASTRA HASSLE AB,CLIN PHARMACOL S-43183 MOLNDAL SWEDEN FLINDERS UNIV S AUSTRALIA,DEPT CLIN PHARMACOL BEDFORD PK SA 5042 AUSTRALIA UNIV BASEL,BIOCTR,DEPT PHARMACOL CH-4056 BASEL SWITZERLAND
Titolo Testata:
British journal of clinical pharmacology
fascicolo: 6, volume: 36, anno: 1993,
pagine: 521 - 530
SICI:
0306-5251(1993)36:6<521:IOHLCI>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
HYDROXYLATION POLYMORPHISM; POOR METABOLIZERS; C-14 OMEPRAZOLE; ACID-SECRETION; MEPHENYTOIN; MICROSOMES; RANITIDINE; INHIBITOR; OXIDATION; INVITRO;
Keywords:
OMEPRAZOLE; HUMAN MICROSOMAL METABOLISM; KINETICS; CYP ISOFORMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
T. Andersson et al., "IDENTIFICATION OF HUMAN LIVER CYTOCHROME-P450 ISOFORMS MEDIATING OMEPRAZOLE METABOLISM", British journal of clinical pharmacology, 36(6), 1993, pp. 521-530

Abstract

1 The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the major omeprazole metabolites. 2 The four major metabolites identified in vitro, in tentative order of importance, were hydroxyomeprazole, omeprazole sulphone, 5-O-desmethylomeprazole, and an unidentified compound termed metabolite X. Omeprazole pyridone was also detected but could not be quantitated. Incubation of hydroxyomeprazole and omeprazole sulphone with human microsomes resulted in both cases in formation of the hydroxysulphone. The kinetics of formation of the four primary metabolites studied were biphasic suggesting the involvement of multiple CYP isoforms in each case. Further studies used substrate concentrations atwhich the high affinity activities predominated. 3 Formation of the major metabolite, hydroxyomeprazole, was significantly correlated with S-mephenytoin hydroxylase and with benzo[a]pyrene metabolism and CYP3Acontent. Inhibition studies with isoform selective inhibitors also indicated a dominant role of S-mephenytoin hydroxylase with some CYP3A contribution in the formation of hydroxyomeprazole. Correlation and inhibition data for the sulphone and metabolite X were consistent with a predominant role of the CYP3A subfamily in formation of these metabolites. Formation of 5-O-desmethylomeprazole was inhibited by both R, S-mephenytoin and quinidine, indicating that both S-mephenytoin hydroxylase and CYP2D6 may mediate this reaction in human liver microsomes and in vivo. 4 The V(max)/K(m) (indicator of intrinsic clearance in vivo) for hydroxyomeprazole was four times greater than that for omeprazole sulphone. Consistent with findings in vivo, the results predict that omeprazole clearance in vivo would be reduced in poor metabolisers of mephenytoin due to reduction in the dominant partial metabolic clearance to hydroxyomeprazole.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 06:58:46