Prediction of Drug Tissue to Plasma Concentration Ratios Using a Measured Volume of Distribution in Combination With Lipophilicity

Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods

“…The other concept of the novel method proposed in the present study was based on the correlation between Kpu ‐muscle and Kpu ‐lean tissue . This concept has been already characterized of being a valid concept in previous works 7–9. Since the present work demonstrated again relatively strong correlations between Kpu of lean tissues (Tab.…”

“…Using the same principle, muscle as the most abundant distribution organ could also be used as a surrogate for all other lean tissues, when the Kpu in vivo of muscle correlates with both, the RBCu in vitro as well as with the Kpu in vivo of all other lean tissues. Such a strategy would be in line with the already demonstrated correlations between Kpu of muscle and Kpu of nonadipose tissues for several classes of drugs including bases 7–9. Consequently, this suggests that the Kp of muscle could be used as a predictor of the Kp of other organs/tissues under in vivo conditions, which may also facilitate the prediction of V ss prior to the accessibility of in vivo V ss data.…”

“…Assuming that the binding to PhS is the major determinant of tissue distribution of a basic drug in rat tissues and red blood cells,4, 5, 10 it is of interest to verify whether the in vitro RBCu correlates with the in vivo Kpu of lean tissues to develop the new concept to predict rat Kpu values for unbound drugs. Using the same principles, muscle Kpu could also be correlated with Kpu of other tissues, since previous works already demonstrated correlations between Kpu of muscle and Kpu of nonadipose tissues for several classes of drugs including bases 7–9. Correlation analysis indicated that these relationships could not be described by simple linear regression analysis.…”

“…Recent developments of prediction methods for V ss , and in particular for tissue/plasma partition coefficients (Kp) of several tissues, allow now predicting V ss of a drug in animal and human already at early stages of drug discovery and development 2–10. Despite the success of those established prediction methods, basic drugs (at least one p K a ≥ 7) remain to be a major challenge to predict their distribution behavior, primarily because of their ionic interactions with acidic phospholipids, which are the main determinants of their tissue distribution under in vivo condition 4, 5, 10.…”

Estimating Unbound Volume of Distribution and Tissue Binding by In Vitro HPLC-Based Human Serum Albumin and Immobilised Artificial Membrane-Binding Measurements

“…There are several other approaches [25][26][27][28][29] for the estimation of human pharmaco-kinetics and various tissue distributions, such as physiological based pharmaco-kinetic modelling (PBPK) using various physico-chemical, preclinical and in vivo data, 30 which are outside the scope of our approach.…”