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

Prashant B. Nigade, Jayasagar Gundu, K. Sreedhara Pai, Kumar V.S. Nemmani

Research output: Contribution to journalArticle

2 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)835-847
Number of pages13
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
Volume42
Issue number5
DOIs
Publication statusPublished - 01-10-2017

Fingerprint

Muscles
Organ Size
Skin
Brain
Pharmaceutical Preparations
Oral Administration
Linear Models
Spleen
Lung
Liver

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Nigade, Prashant B. ; Gundu, Jayasagar ; Sreedhara Pai, K. ; Nemmani, Kumar V.S. / Prediction of Tissue-to-Plasma Ratios of Basic Compounds in Mice. In: European Journal of Drug Metabolism and Pharmacokinetics. 2017 ; Vol. 42, No. 5. pp. 835-847.
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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-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.",
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Prediction of Tissue-to-Plasma Ratios of Basic Compounds in Mice. / Nigade, Prashant B.; Gundu, Jayasagar; Sreedhara Pai, K.; Nemmani, Kumar V.S.

In: European Journal of Drug Metabolism and Pharmacokinetics, Vol. 42, No. 5, 01.10.2017, p. 835-847.

Research output: Contribution to journalArticle

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