{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jeong YS"],"funding":["NIGMS NIH HHS"],"pagination":["463-479"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9014445"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["39(3)"],"pubmed_abstract":["<h4>Purpose</h4>The tissue-to-plasma partition coefficient (K<sub>p</sub>) 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<sub>p,ss</sub>, while the tissue-plasma concentration ratio (C<sub>T</sub>/C<sub>p</sub>) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C<sub>T</sub>/C<sub>p</sub> to K<sub>p,ss</sub> based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (Q<sub>T</sub>) and apparent tissue permeability (f<sub>up</sub>PS<sub>in</sub>) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (f<sub>d</sub>).<h4>Methods</h4>Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of C<sub>T</sub>/C<sub>p</sub> values to K<sub>p,ss</sub>. The relationships were demonstrated in rats with measured C<sub>T</sub>/C<sub>p</sub> and K<sub>p,ss</sub> values and the model-dependent f<sub>d</sub> for 8 compounds with a range of permeability coefficients. Several methods of assessing K<sub>p</sub> were compared.<h4>Results</h4>Utilizing f<sub>d</sub> in an extended C&G method, our estimations of K<sub>p,ss</sub> from C<sub>T</sub>/C<sub>p</sub> were improved, particularly for lower permeability compounds. However, four in silico methods for estimating K<sub>p</sub> performed poorly across tissues in comparison with measured K<sub>p</sub> values. Mathematical relationships between K<sub>p</sub> and K<sub>p,ss</sub> that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and f<sub>d</sub>.<h4>Conclusion</h4>Since many different types/sources of K<sub>p</sub> are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting K<sub>p</sub> values in PBPK."],"journal":["Pharmaceutical research"],"pubmed_title":["Consideration of Fractional Distribution Parameter f<sub>d</sub> in the Chen and Gross Method for Tissue-to-Plasma Partition Coefficients: Comparison of Several Methods."],"pmcid":["PMC9014445"],"funding_grant_id":["R35 GM131800"],"pubmed_authors":["Jusko WJ","Jeong YS"],"additional_accession":[]},"is_claimable":false,"name":"Consideration of Fractional Distribution Parameter f<sub>d</sub> in the Chen and Gross Method for Tissue-to-Plasma Partition Coefficients: Comparison of Several Methods.","description":"<h4>Purpose</h4>The tissue-to-plasma partition coefficient (K<sub>p</sub>) 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<sub>p,ss</sub>, while the tissue-plasma concentration ratio (C<sub>T</sub>/C<sub>p</sub>) in the terminal phase after intravenous doses is often utilized. The Chen and Gross (C&G) method converts a terminal slope C<sub>T</sub>/C<sub>p</sub> to K<sub>p,ss</sub> based on assumptions of perfusion-limited distribution in tissue-plasma equilibration. However, considering blood flow (Q<sub>T</sub>) and apparent tissue permeability (f<sub>up</sub>PS<sub>in</sub>) in the rate of tissue distribution, this report extends the C&G method by utilizing a fractional distribution parameter (f<sub>d</sub>).<h4>Methods</h4>Relevant PBPK equations for non-eliminating and eliminating organs along with lung and liver were derived for the conversion of C<sub>T</sub>/C<sub>p</sub> values to K<sub>p,ss</sub>. The relationships were demonstrated in rats with measured C<sub>T</sub>/C<sub>p</sub> and K<sub>p,ss</sub> values and the model-dependent f<sub>d</sub> for 8 compounds with a range of permeability coefficients. Several methods of assessing K<sub>p</sub> were compared.<h4>Results</h4>Utilizing f<sub>d</sub> in an extended C&G method, our estimations of K<sub>p,ss</sub> from C<sub>T</sub>/C<sub>p</sub> were improved, particularly for lower permeability compounds. However, four in silico methods for estimating K<sub>p</sub> performed poorly across tissues in comparison with measured K<sub>p</sub> values. Mathematical relationships between K<sub>p</sub> and K<sub>p,ss</sub> that are generally applicable for eliminating organs with tissue permeability limitations necessitates inclusion of an extraction ratio (ER) and f<sub>d</sub>.<h4>Conclusion</h4>Since many different types/sources of K<sub>p</sub> are present in the literature and used in PBPK models, these perspectives and equations should provide better insights in measuring and interpreting K<sub>p</sub> values in PBPK.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2025-04-19T16:36:48.864Z","creation":"2025-04-19T16:36:48.864Z"},"accession":"S-EPMC9014445","cross_references":{"pubmed":["35288804"],"doi":["10.1007/s11095-022-03211-3"]}}