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Accounting for Transporters in Renal Clearance: Towards a Mechanistic Kidney Model (Mech KiM)

  • Sibylle NeuhoffEmail author
  • Lu Gaohua
  • Howard Burt
  • Masoud Jamei
  • Linzhong Li
  • Geoffrey T. Tucker
  • Amin Rostami-Hodjegan
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 7)

Abstract

The impact of transporters in modulating the disposition of drugs in the liver and their passage across the gut wall has received much more attention than their role in renal excretion, despite the fact that 25–30 % of drugs are cleared predominantly by renal clearance and renal transporters contribute significantly to this process. Thus there is a need to improve the ability to predict changes in renal clearance arising from genetic variability, the impact of disease and interactions related to renal transporters. Such changes may also influence the accumulation of xenobiotics within the kidney cell leading to nephrotoxicity. Attempts to develop mechanistic, physiologically based models of renal drug elimination have been limited. This chapter outlines the features and application of a new model (Mech KiM) that links drug characteristics to knowledge of renal physiology in predicting the contributions of glomerular filtration, active and passive secretion, active and passive reabsorption and metabolism to renal elimination.

Keywords

Proximal Tubule Renal Clearance Distal Tubule Quantitative Structure Activity Relationship Model Proximal Tubular Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CLPD

Passive diffusion clearance

CYP450

Cytochrome P450

GFR

Glomerular filtration rate

ISEF-T

Inter-system extrapolation factor for transporters

IVIVE

In vitro–in vivo extrapolation

MATE

Multidrug and toxin extruder

MDRD

Modification of diet in renal disease

PBPK

Physiologically based pharmacokinetics

PTCPGK

Proximal tubular cells per gram of kidney

QSAR

Quantitative structure activity relationship

RAF

Relative activity factor

REF

Relative expression factor

tDDI

Transporter-mediated drug–drug interaction

UGT

Uridine glucuronosyltransferase

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sibylle Neuhoff
    • 1
    Email author
  • Lu Gaohua
    • 1
  • Howard Burt
    • 1
  • Masoud Jamei
    • 1
  • Linzhong Li
    • 1
  • Geoffrey T. Tucker
    • 1
    • 2
  • Amin Rostami-Hodjegan
    • 1
    • 3
  1. 1.Simcyp Limited, Blades Enterprise CentreSheffieldUK
  2. 2.Clinical Pharmacology, School of Medicine and Biomedical SciencesUniversity of SheffieldSheffieldUK
  3. 3.Faculty of Medical and Human Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity of Manchester StopfordManchesterUK

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