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

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Transporters in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences 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.

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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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Authors and Affiliations

  1. Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK

    Sibylle Neuhoff, Lu Gaohua, Howard Burt, Masoud Jamei, Linzhong Li, Geoffrey T. Tucker & Amin Rostami-Hodjegan

  2. Clinical Pharmacology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK

    Geoffrey T. Tucker

  3. Faculty of Medical and Human Sciences, School of Pharmacy and Pharmaceutical Sciences, University of Manchester Stopford, Manchester, UK

    Amin Rostami-Hodjegan

Authors
  1. Sibylle Neuhoff
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  2. Lu Gaohua
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  3. Howard Burt
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  4. Masoud Jamei
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  5. Linzhong Li
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  6. Geoffrey T. Tucker
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  7. Amin Rostami-Hodjegan
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Corresponding author

Correspondence to Sibylle Neuhoff .

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Editors and Affiliations

  1. The University of Tokyo Graduate School of Pharmac. Sciences, Tokyo, Japan

    Yuichi Sugiyama

  2. Pharma, Drug Transporters in ADME Department of Pharmacy, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark

    Bente Steffansen

Appendix

Appendix

IVIVE for renal transporters using rhTransporter cell systems such as CHO-OAT1, HEK293-OAT3, etc.

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Neuhoff, S. et al. (2013). Accounting for Transporters in Renal Clearance: Towards a Mechanistic Kidney Model (Mech KiM). In: Sugiyama, Y., Steffansen, B. (eds) Transporters in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8229-1_7

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