Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models

Pai, Sreedhara K (2018) Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models. European Journal of Drug Metabolism and Pharmacokinetics (43). pp. 331-346. ISSN 0378-7966

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Abstract

Background Predicting target site drug concentrations is of key importance for rank ordering compounds before proceeding to chronic pharmacodynamic models. We propose generic tumor-specific correlation-based regression equations to predict tumor-to-plasma ratios (tumor-Kps) in slow- and fast-growing xenograft mouse models. Methods Disposition of 14 basic small molecules was investigated extensively in mouse plasma, tissues and tumors after a single oral dose administration. Linear correlation was assessed and compared between tumor-Kp and normal tissue-to-plasma ratio (tissue-Kps) separately for each tumor xenograft. The developed regression equations were validated by leave-one-out cross-validation (LOOCV)method. Result Both slow- and fast-growing tumor-Kps showed good correlation (r 2 C 0.7) with majority of the normal tissue-Kps. Substantial difference was observed in the slopes of developed equations between two xenografts, which was in line with observed difference in tumor distribution. The linear correlations between tumor-Kp and skin- or spleen-Kp were within the acceptable statistical criteria (LOOCV) across xenografts and the class of compounds evaluated. Since[70% of tumor-Kps from the test data sets were predicted within a factor of twofold for both slow- and fast-growing xenograft mouse models, the results validate the applicability of the developed equations across xenografts.Conclusion Tumor-specific correlation-based regression equations were developed and their applicability was adequately validated across xenografts. These equations could be successfully translated to predict tumor concentrations in order to preclude experimental tumor-Kp determination.

Item Type: Article
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 23 Aug 2018 11:16
Last Modified: 23 Aug 2018 11:16
URI: http://eprints.manipal.edu/id/eprint/151855

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