Impact of Plasma Protein Binding in Drug Clearance Prediction: A Data Base Analysis of Published Studies and Implications for In Vitro-In Vivo Extrapolation
| Autor: | Houston Jb, Laura Francis, David Hallifax |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Data Analysis
Databases Factual Metabolic Clearance Rate Database analysis Extrapolation Pharmaceutical Science Drug Elimination Routes Plasma protein binding 030226 pharmacology & pharmacy 03 medical and health sciences 0302 clinical medicine In vivo Animals Humans In vitro in vivo Pharmacology Chemistry Blood Proteins Blood proteins In vitro Rats Pharmaceutical Preparations 030220 oncology & carcinogenesis Hepatocytes Biophysics Forecasting Protein Binding Clearance |
| Zdroj: | Drug Metabolism and Disposition. 49:188-201 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.120.000294 |
| Popis: | Plasma protein-mediated uptake (PMU) and its effect on clearance (CL) prediction have been studied in various formats; however, a comprehensive analysis of the overall impact of PMU on CL parameters from hepatocyte assays (routinely used for IVIVE) has not previously been performed. The following work collated data reflecting the effect of PMU for 26 compounds with a wide variety of physicochemical, drug, and in vivo CL properties. PMU enhanced the unbound intrinsic clearance in vitro (CLint,u in vitro) beyond that conventionally calculated using fraction unbound and was correlated with the unbound fraction of drug in vitro and in plasma (fup) and absolute unbound intrinsic clearance in vivo (CLint,u in vivo) in both rat and human hepatocytes. PMU appeared to be more important for highly bound (fup 50% of compounds predicted within a 2-fold error for both rat and human data sets (n ≥ 100). SIGNIFICANCE STATEMENT: Current strategies for prediction of hepatic clearance from in vitro data are recognized to be inaccurate, but they do not account for PMU. The impact of PMU on CLint,u in vitro is wide ranging and can be predicted based on fraction unbound in plasma and applied to CLint,u in vitro values obtained by standard procedures in the absence of plasma protein. Such PMU-enhanced predictions improved IVIVE, and future studies may easily incorporate this PMU relationship to provide more accurate IVIVE. |
| Databáze: | OpenAIRE |
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