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 biologic 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, pharmacodynamics, and efficacy relations. Fraction unbound ( ) 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 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 between tumors and the possibility of surrogate tissue(s) for tumor (f) determination. The crosstumor comparison showed that f values across tumors are largely comparable, and systematic tissue versus tumor comparison demonstrated that only lung tissue had comparable to all five tumors ( values within twofold change for >80% compounds in both comparisons). These results indicated that mouse lung tissue can be used as a surrogate matrix for a f assay. This study will increase efficiency in f assessment and reduce animal use (adapting the replace, reduce, and refine principle) in drug discovery. SIGNIFICANCE STATEMENT: The free drug concept is a well accepted principle in drug discovery research. Currently, tumor fraction unbound (f) is determined in several tumors derived from different cell lines to estimate free drug concentrations of a compound. The results from this study indicated that f across xenografted tumors is comparable, and f can be estimated using a surrogate tissue, mouse lung. The results will increase efficiency in f assessment and reduce animal use in drug discovery.