Quantitative in vitro to in vivo extrapolation of cell-based toxicity assay results.
Crit Rev Toxicol
; 42(8): 633-52, 2012 Sep.
Article
em En
| MEDLINE
| ID: mdl-22667820
ABSTRACT
The field of toxicology is currently undergoing a global paradigm shift to use of in vitro approaches for assessing the risks of chemicals and drugs in a more mechanistic and high throughput manner than current approaches relying primarily on in vivo testing. However, reliance on in vitro data entails a number of new challenges associated with translating the in vitro results to corresponding in vivo exposures. Physiologically based pharmacokinetic (PBPK) modeling provides an effective framework for conducting quantitative in vitro to in vivo extrapolation (QIVIVE). Their physiological structure facilitates the incorporation of in silico- and in vitro-derived chemical-specific parameters in order to predict in vivo absorption, distribution, metabolism and excretion. In particular, the combination of in silico- and in vitro parameter estimation with PBPK modeling can be used to predict the in vivo exposure conditions that would produce chemical concentrations in the target tissue equivalent to the concentrations at which effects were observed with in vitro assays of tissue/organ toxicity. This review describes the various elements of QIVIVE and highlights key aspects of the process, with an emphasis on extrapolation of in vitro metabolism data to predict in vivo clearance as the key element. Other important elements include characterization of free concentration in the toxicity assay and potential complications associated with intestinal absorption and renal clearance. Examples of successful QIVIVE approaches are described ranging from a simple steady-state approach that is suitable for a high throughput environment to more complicated approaches requiring full PBPK models.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Testes de Toxicidade
/
Poluentes Ambientais
/
Estudos de Avaliação como Assunto
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
/
Evaluation_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Crit Rev Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos