Simultaneous determination of the inhibitory potency of compounds on the activity of five cytochrome P-450 enzymes using a cocktail probe substrates method / 药学学报
Acta Pharmaceutica Sinica
;
(12): 589-594, 2007.
Artículo
en Chino
| WPRIM
| ID: wpr-281871
ABSTRACT
This study developed a method for simultaneously assessing the inhibitory potency of compounds on five major cytochrome P-450 ( CYP450) enzymes using a cocktail of probe substrates. A cocktail selective substrates consisting of the phenacetin (PN, CYP1A2), dextromethorphan (DM, CYP2D6), tolbutamide (TB, CYP2C9), omeprazole (OPZ, CYP2C19) and midazolam (MPZ, CYP3A4) was incubated with human liver microsomes. The concentrations of the substrate metabolites paracetamol, dextrorphan, 4-hydroxytolbutamide, 5-hydroxyomeprazole and 1'-hydroxymidazolam were determined by LC/MS/MS in a single assay sample. The method was validated by incubating known CYP inhibitors--alpha-naphthoflavone (ANF, CYP1A2), quinidine (QND, CYP2D6), sulfaphenazole (SUL, CYP2C9), fluconazole (FLU, CYP2C19) and ketoconazole (KET, CYP3A4) with the individual substrates and with the substrate cocktail. The IC50 values were then determined. The IC50s (micromol x L(-1)) were in good agreement with those obtained with individual substrates (alpha-naphthoflavone, 0.18 vs 0.26; quinidine, 0.058 5 vs 0.058 4; sulfaphenazole, 0.48 vs 0.45; fluconazol, 17.5 vs 11.4; ketoconazole, 0.22 vs 0.24) and with previously reported values in the literature. This cocktail probe substrate method can be utilized for the rapid simultaneous determination of the inhibition potential of compounds on the five CYP450 enzymes.
Texto completo:
Disponible
Índice:
WPRIM (Pacífico Occidental)
Asunto principal:
Farmacología
/
Cromatografía Liquida
/
Concentración 50 Inhibidora
/
Inhibidores Enzimáticos
/
Espectrometría de Masas en Tándem
/
Inhibidores Enzimáticos del Citocromo P-450
Límite:
Humanos
Idioma:
Chino
Revista:
Acta Pharmaceutica Sinica
Año:
2007
Tipo del documento:
Artículo
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