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Xenografted Tumors Share Comparable Fraction Unbound and Can Be Surrogated by Mouse Lung Tissue .
Free (unbound) drug concentration at the site of action is the key determinant of biological activity since only unbound drugs can exert pharmacological and toxicological effects. Unbound drug concentration in tumors for solid cancers is needed to understand/explain/predict pharmacokinetics (PK), pharmacodynamics (PD), and efficacy relations. Fraction unbound (fu ) in tumors is usually determined across several xenografted tumors derived from various cell lines in the drug discovery stage, which is time-consuming and a resource burden. In this study, we determined the fu values for a set of diverse compounds (comprising acid, base, neutral, zwitterion, and covalent drugs) across five different xenografted tumors and five commercially available mouse tissues to explore the correlation of fu between tumors and the possibility of surrogate tissue(s) for tumor fu (fu,tumor ) determination. The cross-tumor comparison showed fu,tumor values across tumors are largely comparable, and systematic tissue vs. tumor comparison demonstrated only lung tissue had comparable fu to all five tumors (fu values within 2-fold change for >80% compounds in both comparisons). These results indicated mouse lung tissue can be used as a surrogate matrix for fu,tumor assay. This study will increase efficiency in fu,tumor assessment and reduce animal use (adapting the 3Rs principle: replace, reduce, and refine) in drug discovery Significance Statement The free drug concept is a well-accepted principle in drug discovery research. Currently, fu,tumor is determined in several tumors derived from different cell lines to estimate free drug concentrations of a compound. The results from this study indicated fu,tumor across xenografted tumors are comparable and fu,tumor can be estimated using a surrogate tissue, mouse lung. The results will increase efficiency in fu,tumor assessment and reduce animal use in drug discovery.
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