A New Guidance for the Prediction of Hepatic Clearance in the Early Drug Discovery and Development from the in Vitro-to-in Vivo Extrapolation Method and an Approach for Exploring Whether an Albumin-Mediated Hepatic Uptake Phenomenon Could be Present Under in Vivo Conditions.
J Pharm Sci
; 110(7): 2841-2858, 2021 07.
Article
em En
| MEDLINE
| ID: mdl-33857483
ABSTRACT
The in vitro-to-in vivo extrapolation (IVIVE) methods for predicting the hepatic clearance (CL) of drugs based on microsomal or hepatocyte data have certainly advanced; however, there is still place for improving the extrapolations from in vitro assays containing no plasma proteins. Accordingly, there is a discussion on whether the free drug hypothesis or an albumin (ALB)-mediated hepatic uptake phenomenon is the best scaling method. Therefore, the objectives of this study were to guide the prediction of CL and to diagnose which scaling method between the free drug hypothesis and ALB-mediated uptake could be more accurate; this, irrespective of the mechanism(s) governing CL if the drugs can get to the hepatocyte membrane. The analysis of several datasets demonstrated that almost all values of CL in vivo fall within the two calculated values of CL use as boundaries from 1) the free drug hypothesis, and 2) ALB-mediated uptake. The average value from these two CL boundaries predicted the CL in vivo with an incredible accuracy. Validating these boundaries in preclinical species prior going to human as well as considering the fractional binding in plasma increased the accuracy. Overall, this study is another step towards guiding the CL prediction in drug discovery and development.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Preparações Farmacêuticas
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Descoberta de Drogas
Tipo de estudo:
Guideline
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Prognostic_studies
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Qualitative_research
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Pharm Sci
Ano de publicação:
2021
Tipo de documento:
Article