Linking biomimetic binding measurements to pharmacokinetic models of volume of distribution and hepatic clearance.

Background and purpose: The steady-state volume of distribution reflects the extent to which drugs partition between plasma and tissues and is closely related to the tissue-to-plasma partition coefficient. In pharmacokinetics, different modelling frameworks have led to ongoing debate regarding the role of plasma protein binding and the importance of unbound drug exposure in determining both distribution and clearance. This review aims to clarify the relationship between distribution and elimination models and to assess how experimental binding measurements can support their mechanistic interpretation. Experimental approach: Established pharmacokinetic relationships linking volume of distribution ( Key results: The analysis shows that distribution and clearance models describe complementary aspects of drug disposition rather than contradictory processes. Tissue binding, as reflected by phospholipid affinity measured by IAM chromatography, plays a dominant role in determining Conclusion: This work demonstrates that biomimetic binding measurements provide a mechanistically meaningful bridge between physicochemical properties and pharmacokinetic behaviour. By integrating experimental binding data with pharmacokinetic models, the study advances understanding of how distribution and clearance are linked, supporting more informed decision-making in early drug discovery while highlighting that clearance remains influenced by additional factors beyond non-specific binding.