Clinical Pharmacokinetics

, Volume 53, Issue 3, pp 283–293 | Cite as

Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations

  • Vicky Hsu
  • Manuela de L. T. Vieira
  • Ping ZhaoEmail author
  • Lei Zhang
  • Jenny Huimin Zheng
  • Anna Nordmark
  • Eva Gil Berglund
  • Kathleen M. Giacomini
  • Shiew-Mei Huang
Original Research Article


Background and Objectives

The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters.


Models for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (Tup,b) and apical efflux transport (Teff,a) being specifically defined.

Results and Conclusion

We demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (≥10-fold reduction in the functional ‘proximal tubule cells per gram kidney’) in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of Tup,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting Tup,b in order to alleviate cidofovir-induced nephrotoxicity.


Renal Impairment Cefuroxime Probenecid PBPK Modelling Severe Renal Impairment 
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.



Area under the concentration–time curve


Blood to plasma partition ratio


Creatinine clearance


Transporter-mediated intrinsic clearance


In vivo clearance


Passive diffusion clearance


Renal clearance


Renal clearance mediated by a transporter


Drug–drug interaction


Fraction available from dosage form


Fraction unbound in plasma


Glomerular filtration rate


Plasma unbound inhibitor concentration


First-order absorption rate constant


Reversible inhibition constant


Tissue-to-plasma partition coefficient


Partition coefficient


Organic anion transporter


Dissociation constant


Physiologically based pharmacokinetic modelling


Proximal tubular cells per gram kidney


Renal impairment


Efflux transporter on apical membrane


Uptake transporter on basolateral membrane


Volume of distribution at steady state



The authors gratefully acknowledge Professor Amin Rostami-Hodjegan (from the University of Manchester, Manchester, UK) and Drs Sibylle Neuhoff and Masoud Jamei (from Simcyp Ltd, Sheffield, UK) for their scientific input. This research was supported by the US Food and Drug Administration’s (FDA’s) Medical Countermeasures initiative. Dr Vicky Hsu was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. No official support or endorsement by the FDA or the Medical Products Agency is intended or should be inferred.

Conflicts of Interest

The authors have declared no conflict of interest.

Author Contributions

Vicky Hsu, Manuela de L. T. Vieira and Ping Zhao designed the research, performed the research, analysed the data, contributed new reagents/analytical tools and participated in the writing of the manuscript. Lei Zhang, Jenny Huimin Zheng, Anna Nordmark, Eva Gil Berglund, Kathleen M. Giacomini and Shiew-Mei Huang analysed the data and participated in the writing of the manuscript. All authors read and approved the final manuscript.

Supplementary material

40262_2013_117_MOESM1_ESM.docx (426 kb)
Supplementary material 1 (PDF 245 kb)


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Authors and Affiliations

  • Vicky Hsu
    • 1
  • Manuela de L. T. Vieira
    • 1
    • 2
  • Ping Zhao
    • 1
    Email author
  • Lei Zhang
    • 1
  • Jenny Huimin Zheng
    • 1
  • Anna Nordmark
    • 3
  • Eva Gil Berglund
    • 3
  • Kathleen M. Giacomini
    • 4
  • Shiew-Mei Huang
    • 1
  1. 1.Office of Clinical Pharmacology, Office of Translational SciencesCenter for Drug Evaluation and Research, US Food and Drug AdministrationSilver SpringUSA
  2. 2.College of PharmacyFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Swedish Medical Products AgencyUppsalaSweden
  4. 4.Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and MedicineUniversity of California San FranciscoSan FranciscoUSA

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