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 r2 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 (<0.5-fold) for liver, spleen and lung, respectively. Whereas 63 and 75% data points were over 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.
|Number of pages
|European Journal of Drug Metabolism and Pharmacokinetics
|Published - 01-10-2017
All Science Journal Classification (ASJC) codes
- Pharmacology (medical)