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Drug Metab Lett ; 5(1): 17-24, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21198441

RESUMO

A validated method for the simultaneous characterization of xenobiotic compound-mediated inhibition of seven major cytochrome P450 (CYP) enzymes in pooled human liver microsomes through the use of specific CYP probe substrates (cocktail assay) with low protein content, and a rapid, three minute LC-MS/MS analytical method is described. The specific CYP substrates used in this cocktail assay included phenacetin (CYP1A2), bupropion (CYP2B6), amodiaquine (CYP2C8), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4/5). The LC-MS method incorporated the aforementioned seven CYP substrates along with their respective major metabolites, and one internal standard, labetalol. In a cross-validation analysis, the concentrations of each CYP probe substrate in the assay had minimal effect (i.e., inhibition or activation) on the other CYP activities. Furthermore, the assay conditions for the multiple probe substrate, ie., cocktail assay, were validated against the single probe substrate assay using 18 compounds with known CYP inhibition liabilities and 10 proprietary compounds. The inhibitory constant (Ki) determined with this cocktail assay was highly correlated (R(2) ≥ 0.77 for each individual probe substrate) with that of the single probe substrate assay for all 27 CYP inhibitors. This seven CYP inhibition cocktail assay has increased the efficiency to assess compounds for inhibition of the major CYP isoforms in a high throughput, drug discovery setting.


Assuntos
Cromatografia Líquida , Inibidores das Enzimas do Citocromo P-450 , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Microssomos Hepáticos/efeitos dos fármacos , Espectrometria de Massas em Tandem , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Técnicas In Vitro , Isoenzimas , Cinética , Microssomos Hepáticos/enzimologia , Sondas Moleculares/metabolismo , Reprodutibilidade dos Testes , Especificidade por Substrato
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