Prediction of tissue-to-plasma ratios of basic compounds in mice

Pai, Sreedhara Ranganath K (2017) Prediction of tissue-to-plasma ratios of basic compounds in mice. European Journal of Drug Metabolism and Pharmacokinetics, 42 (5). pp. 835-847. 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 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 Kpmuscle 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 bloodflowand inversely to the organweight. 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.

Item Type: Article
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 19 Sep 2017 10:55
Last Modified: 19 Sep 2017 10:55
URI: http://eprints.manipal.edu/id/eprint/149719

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