Prediction of V(ss) from in vitro tissue-binding studies.
Drug Metab Dispos
; 38(1): 115-21, 2010 Jan.
Article
en En
| MEDLINE
| ID: mdl-19797608
ABSTRACT
To predict volume of distribution at steady-state (V(ss)), empirical (e.g., allometry) and mechanistic (using physicochemical property data and plasma protein binding) methods have been used. None of these approaches has been able to predict V(ss) accurately for the total compliment of a wide range of drugs. Therefore, alternative approaches would be of value. This study evaluates the utility of in vitro nonspecific tissue-binding measurements in predicting V(ss) for a wide range of drugs in rats. Literature as well as proprietary compounds were studied. It was found that in vitro tissue-binding measurements combined with calculated effects of the pH partition hypothesis often predict V(ss) more accurately than other available mechanistic methods and that this approach can compliment existing methods. The V(ss) values for some compounds were not accurately predicted using either nonspecific tissue-binding experiments or other available mechanistic methods. The V(ss) for these drugs may not be describable by nonspecific tissue binding alone; there may be significant specific components to the mechanism of distribution for these drugs, such as pH-dependent uptake into lysosomes (primarily strongly basic drugs), active transport, and/or enterohepatic recirculation. A lack of prediction for certain drugs warrants further investigation into these mechanisms and their application to more accurate prediction of V(ss) by mechanistic means.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Extractos de Tejidos
/
Farmacocinética
/
Preparaciones Farmacéuticas
/
Modelos Biológicos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos