Consideration of Fractional Distribution Parameter f d in the Chen and Gross Method for Tissue-to-Plasma Partition Coefficients: Comparison of Several Methods.

Purpose: The tissue-to-plasma partition coefficient (K _p ) describes the extent of tissue distribution in physiologically-based pharmacokinetic (PBPK) models. Constant-rate infusion studies are common for experimental determination of the steady-state K _p,ss , while the tissue-plasma concentration ratio (C _T /C _p ) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C _T /C _p to K _p,ss based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (Q _T ) and apparent tissue permeability (f _up PS _in ) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (f _d ).
Methods: Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of C _T /C _p values to K _p,ss . The relationships were demonstrated in rats with measured C _T /C _p and K _p,ss values and the model-dependent f _d for 8 compounds with a range of permeability coefficients. Several methods of assessing K _p were compared.
Results: Utilizing f _d in an extended C&G method, our estimations of K _p,ss from C _T /C _p were improved, particularly for lower permeability compounds. However, four in silico methods for estimating K _p performed poorly across tissues in comparison with measured K _p values. Mathematical relationships between K _p and K _p,ss that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and f _d .
Conclusion: Since many different types/sources of K _p are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting K _p values in PBPK.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)