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Titolo:
USE OF HETEROLOGOUSLY EXPRESSED HUMAN CYTOCHROME-P450 1A2 TO PREDICT TACRINE-FLUVOXAMINE DRUG-INTERACTION IN MAN
Autore:
BECQUEMONT L; LEBOT MA; RICHE C; FUNCKBRENTANO C; JAILLON P; BEAUNE P;
Indirizzi:
HOP ST ANTOINE,UNITE PHARMACOL CLIN,184 RUE FAUBOURG ST ANTOINE F-75012 PARIS FRANCE ST ANTOINE UNIV HOSP,CLIN PHARMACOL UNIT PARIS FRANCE UNIV BREST,SCH MED,DEPT PHARMACOL BREST FRANCE NECKER ENFANTS MALAD UNIV,SCH MED,INSERM,U75 PARIS FRANCE
Titolo Testata:
Pharmacogenetics
fascicolo: 2, volume: 8, anno: 1998,
pagine: 101 - 108
SICI:
0960-314X(1998)8:2<101:UOHEHC>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; IN-VITRO; WARFARIN-FLUCONAZOLE; METABOLISM; INHIBITION; ENZYMES; VIVO; HYDROXYLATION; PHENACETIN; CLEARANCE;
Keywords:
HETEROLOGOUSLY EXPRESSED HUMAN CYTOCHROMES P450; DRUG INTERACTION; TACRINE; FLUVOXAMINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
L. Becquemont et al., "USE OF HETEROLOGOUSLY EXPRESSED HUMAN CYTOCHROME-P450 1A2 TO PREDICT TACRINE-FLUVOXAMINE DRUG-INTERACTION IN MAN", Pharmacogenetics, 8(2), 1998, pp. 101-108

Abstract

The aim of the present study was to evaluate the use of recombinant human cytochrome P-450 1A2 (rH-CYP1A2) in studies performed in vitro inorder to predict metabolic drug-drug interactions occurring in man. In vitro metabolism of tacrine (a CYP1A2 probe) in the presence and absence of fluvoxamine, a CYP1A2 inhibitor, was investigated in human liver mircrosomes and with different rH-CYP. V-max, K-m and K-i determined with human liver microsomes were compared with those observed using rH-CYP1A2, assuming that 1 mg of liver microsomes contains, on average, 69 pmol of CYP1A2. The extent of tacrine metabolism inhibition procured by fluvoxamine with rH-CYP1A2, was compared with previous results observed in man. The V-max and K-m for 1-hydroxytacrine formation rates obtained with rH-CYP1A2 were in good agreement with those observed in human liver microsomes (175 +/- 9 versus 140 +/- 60 pmol/min/mg for V-max and 14 +/- 2 versus 16 +/- 2 mu M for K-m, respectively. The K-iof fluvoxamine on 1-hydroxytacrine formation rate observed with rH-CYP1A2 was similar to that observed with human liver microsome (0.35 +/-0.05 versus 0.20 +/- 0.20 mu M, respectively). Using the K-m, V-max and Ki determined with rH-CYP1A2, we calculated that fluvoxamine produced an inhibition of 1-, 2- and 4-hydroxytacrine formation rate of 91, 87 and 88%, respectively, in the range of tacrine and fluvoxamine concentrations observed in man. These percentages of inhibition calcultated in vitro were in agreement with the percentage of fluvoxamine-dependent decrease in tacrine apparent oral clearance previously observed inman (83 +/- 13%). We conclude that human CYP1A2 expressed in yeast isa powerful tool to predict and to quantify drug-drug interactions in man. Pharmacogenetics 8: 101-108 (C) 1998 Lippincott-Raven Publishers.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/07/20 alle ore 08:55:07