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Titolo:
Substrate-dependent modulation of CYP3A4 catalytic activity: Analysis of 27 test compounds with four fluorometric substrates
Autore:
Stresser, DM; Blanchard, AP; Turner, SD; Erve, JCL; Dandeneau, AA; Miller, VP; Crespi, CL;
Indirizzi:
GENTEST Corp, Woburn, MA 01801 USA GENTEST Corp Woburn MA USA 01801GENTEST Corp, Woburn, MA 01801 USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 28, anno: 2000,
pagine: 1440 - 1448
SICI:
0090-9556(200012)28:12<1440:SMOCCA>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; HUMAN CYTOCHROME-P450 3A4; INHIBITION; ENZYMES; KINETICS; BINDING; IDENTIFICATION; COOPERATIVITY; METABOLISM; OXIDATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Crespi, CL GENTEST Corp, 6 Henshaw St, Woburn, MA 01801 USA GENTEST Corp 6Henshaw St Woburn MA USA 01801 urn, MA 01801 USA
Citazione:
D.M. Stresser et al., "Substrate-dependent modulation of CYP3A4 catalytic activity: Analysis of 27 test compounds with four fluorometric substrates", DRUG META D, 28(12), 2000, pp. 1440-1448

Abstract

Inhibition of cytochrome P450 catalytic activity is a principal mechanism for pharmacokinetic drug-drug interactions. Rapid, in vitro testing for cytochrome P450 inhibition potential is part of the current paradigm for identifying drug candidates likely to give such interactions. We have explored the extent that qualitative and quantitative inhibition parameters are dependent on the cytochrome P450 (CYP) 3A4 probe substrate. Inhibition potential(e.g., IC50 values from 8-point inhibition curves) or activation potentialfor most compounds varied dramatically depending on the fluorometric probesubstrates for CYP3A4 [benzyloxyresorufin (BzRes), 7-benzyloxy-4-trifluoromethylcoumarin (BFC), 7-benzyloxyquinoline (BQ), and dibenzylfluorescein (DBF)]. For 21 compounds that were primarily inhibitors, the range of IC50 values for the four substrates varied from 2.1- to 195-fold with an average of 29-fold. While the rank order of sensitivity among the fluorometric substrates varied among the individual inhibitors, on average, BFC dealkylation was the most sensitive to inhibition, while BQ dealkylation was least sensitive. Partial inhibition was observed with BzRes and BQ but not for BFC andDBF. BzRes was more prone to activation, whereas dramatic changes in IC50 values were observed when the BQ concentration was below the S-50. Three different correlation analyses indicated that IC50 values with BFC, BQ, and DBF correlated well with each other, whereas the response with BzRes correlated more weakly with the other substrates. One of these correlation analyses was extended to the percent inhibition of 10 muM inhibitor with the standard CYP3A4 probe substrates testosterone, midazolam, and nifedipine. In this analysis the responses with BQ, BFC and DBF correlated well with testosterone and midazolam but more poorly with nifedipine. In the aggregate, BFC and DBF appear more suitable as an initial screen for CYP3A4 inhibition. However, the substrate-dependent effects reported here and by others indicate that all CYP3A4 inhibition data should be interpreted with caution.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 06:56:08