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Research ArticleMetabolism, Transport, and Pharmacogenomics

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance

Takanobu Matsuzaki, Daniel Scotcher, Adam S. Darwich, Aleksandra Galetin and Amin Rostami-Hodjegan
Journal of Pharmacology and Experimental Therapeutics February 2019, 368 (2) 157-168; DOI: https://doi.org/10.1124/jpet.118.251413
Takanobu Matsuzaki
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (T.M., D.S., A.S.D., A.G., A.R.-H.); Research Laboratories for Development, Shionogi & Co., Ltd., Osaka, Japan (T.M.); and Simcyp Limited (A Certara Company), Sheffield, United Kingdom (A.R.-H.)
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Daniel Scotcher
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (T.M., D.S., A.S.D., A.G., A.R.-H.); Research Laboratories for Development, Shionogi & Co., Ltd., Osaka, Japan (T.M.); and Simcyp Limited (A Certara Company), Sheffield, United Kingdom (A.R.-H.)
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Adam S. Darwich
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (T.M., D.S., A.S.D., A.G., A.R.-H.); Research Laboratories for Development, Shionogi & Co., Ltd., Osaka, Japan (T.M.); and Simcyp Limited (A Certara Company), Sheffield, United Kingdom (A.R.-H.)
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Aleksandra Galetin
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (T.M., D.S., A.S.D., A.G., A.R.-H.); Research Laboratories for Development, Shionogi & Co., Ltd., Osaka, Japan (T.M.); and Simcyp Limited (A Certara Company), Sheffield, United Kingdom (A.R.-H.)
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Amin Rostami-Hodjegan
Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom (T.M., D.S., A.S.D., A.G., A.R.-H.); Research Laboratories for Development, Shionogi & Co., Ltd., Osaka, Japan (T.M.); and Simcyp Limited (A Certara Company), Sheffield, United Kingdom (A.R.-H.)
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This article has a correction. Please see:

  • Correction to “Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance” - March 01, 2019

Abstract

In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CLR has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CLR values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87- and 3.62-fold, respectively. Model simulations captured urine flow–dependent CLR, albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

Footnotes

    • Received June 28, 2018.
    • Accepted November 5, 2018.
  • ↵1 T.M. and D.S. equally contributed to this work.

  • T.M. is an employee of Shionogi & Co., Ltd. D.S. was supported by a Ph.D. studentship from the Biotechnology and Biological Sciences Research Council UK [BB/J500379/1] and AstraZeneca. A.R.-H. is an employee of Simcyp Limited (A Certara Company).

  • https://doi.org/10.1124/jpet.118.251413.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2019 The Author(s).

This is an open access article distributed under the CC BY Attribution 4.0 International license.

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Journal of Pharmacology and Experimental Therapeutics: 368 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 2
1 Feb 2019
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Prediction of Perturbed Drug Renal Clearance

Takanobu Matsuzaki, Daniel Scotcher, Adam S. Darwich, Aleksandra Galetin and Amin Rostami-Hodjegan
Journal of Pharmacology and Experimental Therapeutics February 1, 2019, 368 (2) 157-168; DOI: https://doi.org/10.1124/jpet.118.251413

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Prediction of Perturbed Drug Renal Clearance

Takanobu Matsuzaki, Daniel Scotcher, Adam S. Darwich, Aleksandra Galetin and Amin Rostami-Hodjegan
Journal of Pharmacology and Experimental Therapeutics February 1, 2019, 368 (2) 157-168; DOI: https://doi.org/10.1124/jpet.118.251413
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