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

Purpose: The tissue-to-plasma partition coefficient (K) 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, while the tissue-plasma concentration ratio (C/C) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C/C to K based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (Q) and apparent tissue permeability (fPS) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (f).

Methods: Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of C/C values to K. The relationships were demonstrated in rats with measured C/C and K values and the model-dependent f for 8 compounds with a range of permeability coefficients. Several methods of assessing K were compared.

Results: Utilizing f in an extended C&G method, our estimations of K from C/C were improved, particularly for lower permeability compounds. However, four in silico methods for estimating K performed poorly across tissues in comparison with measured K values. Mathematical relationships between K and K that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and f.

Conclusion: Since many different types/sources of K are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting K values in PBPK.