Prediction of Drug Distribution in Subcutaneous Xenografts of Human Tumor Cell Lines and Healthy Tissues in Mouse: Application of the Tissue Composition-Based Model to Antineoplastic Drugs

Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research

“…The individual tissue:plasma partition coefficients ( K p ) are good indicators of the extent of tissue distribution, and define the overall volume of distribution used to compute the loading dose. Therefore, advanced tissue composition‐based models were developed to predict the K p values of drugs under in vivo conditions on the basis of in vitro and physiological input data . Furthermore, other studies evaluated the utility of in vitro nonspecific tissue‐binding measurements in predicting K p values for a wide range of drugs .…”

“…If this paradigm is also applied in clinical studies, the unbound drug level in the human tissue is the relevant metric to optimize on . As has been repeatedly in recent years, tissue binding may exert a greater influence on distribution and PK of drugs than plasma binding . However, binding data in tissues are rarely available for humans, and, hence, the estimation of the essential unbound fraction in tissues (fu t ) of drugs is limited.…”

“…Hence, the values of fu p and fu t would not be equal because of the dissimilarities in the binding and ionization on both sides of the membrane, and the free drug concentration in plasmas and tissue would differ for the ionizable drugs. In addition, in a dynamic in vivo system, the free drug concentration in plasma and tissue would also be affected by the overall PK effect (e.g., intrinsic clearance) . In this study, however, we will only focus on the dissimilarities in the binding and ionization on both sides of the membrane to explain the differences that were observed between experimentally‐determined fu p and fu t values of drugs in humans.…”

“…As the in vivo K p value equals to the ratio of total concentration between tissue and plasma, or the ratio between fu p and fu t , this parameter K p would deviate from the unity. This is because there are diverse effects on both sides of the membrane, namely, the pH gradient, non‐specific binding to lipids, and binding to plasma proteins or lipoproteins . In this situation, although the fu p will differ to fu t because of the dissimilarities between the proteins and lipids content on both sides of the membrane, and, hence, of the bound drug concentration, the free drug concentration in the aqueous phase would be the same in plasma and tissue at steady state but only for the neutral compounds.…”

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

“…The model resulted in reasonable prediction of K p values in healthy tissues (muscle, lung, liver and brain) and human tumor xenografts (HCT-116, H2122 and PC3) in female nude mice for MTX. However, the model severely underestimated K p value of liver for MTX, probably because of uptake by specific hepatic transporters (e.g., folate transporters) [23]. …”