https://orcid.org/0000-0002-6218-4023
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Abstract
According to the free drug hypothesis (FDH), only free, unbound drug is available to interact with biological targets. This hypothesis is the fundamental principle that continues to explain the vast majority of all pharmacokinetic and pharmacodynamic processes. Under the FDH, the free drug concentration at the target site is considered the driver of pharmacodynamic activity and pharmacokinetic processes. However, deviations from the FDH are observed in hepatic uptake and clearance predictions, where observed unbound intrinsic hepatic clearance (CLint,u) is larger than expected. Such deviations are commonly observed when plasma proteins are present and form the basis of the so-called plasma protein-mediated uptake effect (PMUE). This review will discuss the basis of plasma protein binding as it pertains to hepatic clearance based on the FDH, as well as several hypotheses that may explain the underlying mechanisms of PMUE. Notably, some, but not all, potential mechanisms remained aligned with the FDH. Finally, we will outline possible experimental strategies to elucidate PMUE mechanisms. Understanding the mechanisms of PMUE and its potential contribution to clearance underprediction is vital to improving the drug development process.
Acknowledgments
We thank Colin J. Phipps and Ryota Kikuchi (both are employees of AbbVie) for their critical review of the manuscript, editorial, scientific comments, and discussions.
Disclosure statement
All authors are employees of AbbVie and may own AbbVie stock. AbbVie contributed to the design, participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication. The manuscript contains no proprietary AbbVie data.