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• W2765189811 abstract "Background and Purpose Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. Experimental Approach Previous PBPK model development of enantiomers of a series of seven racemic β‐blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S‐timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D‐optimal design. Key Results Closed‐loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate‐limited models. For some compounds in the testes and gut, a permeability rate‐limited distribution model was required to best fit the data. Parameter estimates of the tissue‐to‐blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady‐state experiments. Conclusions and Implications PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential." @default.
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• W2765189811 date "2017-12-01" @default.
• W2765189811 modified "2023-10-05" @default.
• W2765189811 title "Whole body physiologically based modelling of β-blockers in the rat: events in tissues and plasma following an i.v. bolus dose" @default.
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• W2765189811 doi "https://doi.org/10.1111/bph.14071" @default.
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