Clinical Pharmacokinetics

, Volume 53, Issue 3, pp 283–293

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 Zhao
  • Lei Zhang
  • Jenny Huimin Zheng
  • Anna Nordmark
  • Eva Gil Berglund
  • Kathleen M. Giacomini
  • Shiew-Mei Huang
Original Research Article

Abstract

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.

Methods

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.

Abbreviations

AUC

Area under the concentration–time curve

B/P

Blood to plasma partition ratio

CLCR

Creatinine clearance

CLint,T

Transporter-mediated intrinsic clearance

CLiv

In vivo clearance

CLpd

Passive diffusion clearance

CLr

Renal clearance

CLr,T

Renal clearance mediated by a transporter

DDI

Drug–drug interaction

fa

Fraction available from dosage form

fu,p

Fraction unbound in plasma

GFR

Glomerular filtration rate

[I]

Plasma unbound inhibitor concentration

ka

First-order absorption rate constant

Ki

Reversible inhibition constant

Kp

Tissue-to-plasma partition coefficient

LogP

Partition coefficient

OAT

Organic anion transporter

pKa

Dissociation constant

PBPK

Physiologically based pharmacokinetic modelling

PTCPGK

Proximal tubular cells per gram kidney

RI

Renal impairment

Teff,a

Efflux transporter on apical membrane

Tup,b

Uptake transporter on basolateral membrane

Vss

Volume of distribution at steady state

Supplementary material

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

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Copyright information

© The Author(s) 2013

Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Vicky Hsu
    • 1
  • Manuela de L. T. Vieira
    • 1
    • 2
  • Ping Zhao
    • 1
  • 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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