Development of a detailed physiologically based computational kidney model to describe the renal excretion of hydrophilic agents in rats
Ch. Niederalt(1), K. Claassen(2), L. Kuepfer(1), T. Wendl(1), S. Willmann(1), J. Lippert(1), M. Bräutigam, M. Schultze-Mosgau(3), J. Winkler(1), R. Burghaus(3), H. Pietsch(3), P. Lengsfeld(3)
(1) Bayer Technology Services GmbH, Leverkusen, Germany; (2) Jacobs University, gGmBH Campus Ring 1, Bremen, Germany; (3) Bayer HealthCare AG, Berlin, Germany
Objectives: The aim of the study is to develop a detailed physiologically based computational kidney model in order to simulate the renal excretion process of drugs within whole body physiologically based pharmacokinetic (PBPK) models. As a start, a model of the rat kidney particularly for hydrophilic substances is developed. This model mechanistically describes the concentrating process of the drug within the tubular fluids along the nephrons.
Methods: A computational model of the kidney is established representing the tubular fluid within different tubular segments, interstitial space and vascular space including vasa recta. Urine concentration and fluid reabsorption is triggered by osmolality gradients established by NaCl, urea and the drug. Na+ transport and facilitated urea diffusion is taken into account. Physiologic parameters like blood flows and tissue composition are taken from literature if available [1,2]. Missing parameters are fitted to the osmolality gradient along the cortico-medullary axis in the physiological steady state. The model is evaluated using experimental data from mannitol. [3,4]
Results: The model is able to describe the physiological steady state concentrations of NaCl and urea along the cortico-medullary axis. After application of hydrophilic drugs such as mannitol, the model is able to describe the concentrating process within the tubular fluid and the time resolved diuretic effects caused by this agent.
Conclusions: An initial physiologically based kidney model to be used within whole body PBPK models is available. The model will be extended to other species and to lipophilic drugs which may also undergo active secretion and reabsorption.
References:
[1] W. Pfaller and M. Rittinger. Quantitative morphology of the rat kidney. Int. J. Biochem. 12 (1980), 17-22.
[2] The Quantitative Kidney DataBase: V. Dzodic, S. Hervy, D. Fritsch, H. Khalfallah, M. Thereau and S.R.Thomas. Web-based tools for quantitative renal physiology. Cell Mol. Biol. 50 (2004), 795-800.
[3] J. C. Atherton, R. Green and S. Thomas. Effects of 0.9% saline infusion on urinary and renal tissue composition in the hydropaenic, normal and hydrated conscious rat. J. Physiol. 201 (1970), 45-71
[4] J. C. Atherton, M. A. Hai and S. Thomas. The Time Course of changes in renal tissue composition during mannitol diuresis in the rat. J. Physiol. 197 (1968), 411-428.