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

Pai, Sreedhara K (2017) Prediction of Tissue-to-Plasma Ratios of Basic Compounds in Mice. European Journal of Drug Metabolism and Pharmacokinetics, 42 (5). pp. 835-837. ISSN 0378-7966

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Abstract

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-toplasma 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 tissueKps 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 Kpmuscle and Kp-brain, -spleen, -skin, -liver, -lung, suggesting superior correlation between the tissue-Kps. Order of tissueKps, 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 predictedtissue-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

Item Type: Article
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 23 Aug 2018 11:17
Last Modified: 23 Aug 2018 11:17
URI: http://eprints.manipal.edu/id/eprint/151856

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