Prediction of Tissue-to-Plasma Ratios of Basic Compounds in Mice

Background Majority of reported studies so far developed correlation regression equations using the rat muscle-to-plasma drug concentration ratio (Kp-muscle) to predict tissue-to-plasma drug concentration ratios (Kp-tissues). Use of regression equations derived from rat Kp-muscle may not be ideal to predict the mice tissue-Kps as there are species differences. Objectives (i) To develop the linear regression equations using mouse tissue-Kps; (ii) to assess the correlation between organ blood flow and/or organ weight with tissue-Kps and (iii) compare the observed tissue-Kps from mice with corresponding predicted tissue-Kps using Richter’s rat-Kp specific equations. Method Disposition of 12 small molecules were investigated extensively in mouse plasma and tissues after a single oral dose administration. Linear correlation was assessed for each of the tissue with rest of the other tissues, separately for weak and strong bases. Result Newly developed regression equations using mice tissue-Kps, predicted 79% data points within twofold. As observed correlation r 2 range was 0.75–0.98 between Kp-muscle and Kp-brain, -spleen, -skin, -liver, -lung, suggesting superior correlation between the tissue-Kps. Order of tissue-Kps, showed that tissue concentrations were directly proportional to the organ blood flow and inversely to the organ weight. Further, the observed tissue-Kps from mice were compared with corresponding predicted tissue-Kps using Richter’s rat-Kp specific equations. Overall, 46, 54 and 63% data points were under predicted (twofold) for skin and brain, respectively. These findings suggest that cross species extrapolation predictability is poor. Conclusion All these findings together suggest that mouse specific regression equations developed under controlled experimental conditions could be most appropriate for predicting mouse tissue-Kps for compounds with wide range of volume of distribution.