CYP3A time-dependent inhibition risk assessment validated with 400 reference drugs.
Drug Metab Dispos
; 39(6): 1039-46, 2011 Jun.
Article
en En
| MEDLINE
| ID: mdl-21383203
Although reversible CYP3A inhibition testing is well established for predicting the drug-drug interaction potential of clinical candidates, time-dependent inhibition (TDI) has become the focus of drug designers only recently. Failure of several late-stage clinical candidates has been attributed to TDI, and this mechanism is also suspected to play a role in liver toxicities often observed in preclinical species. Measurement of enzyme inactivation rates (k(inact) and K(I)) is technically challenging, and a great deal of variability can be found in the literature. In this article, we have evaluated the TDI potential for 400 registered drugs using a high-throughput assay format based on determination of the inactivation rate (k(obs)) at a single concentration of test compound (10 µM). The advantages of this new assay format are highlighted by comparison with data generated using the IC50 shift assay, a current standard approach for preliminary assessment of TDI. With use of an empirically defined positive/negative k(obs) bin of 0.02 min⻹, only 4% of registered drugs were found to be positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of identifying this property in selection of promising drug candidates. Finally, it is suggested that the data and technology described here may be a good basis for building structure-activity relationships and in silico modeling.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos
/
Inhibidores del Citocromo P-450 CYP3A
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Estados Unidos