The AAPS Journal

, Volume 15, Issue 1, pp 278–287 | Cite as

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

  • Melanie A. Felmlee
  • Rutwij A. Dave
  • Marilyn E. Morris
Research Article Theme: Kidney Transporters: Importance in Clearance, Disease, and Drug-Drug Interactions

Abstract

The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis–Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CLr) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1–1,000 mg/kg) was evaluated, and V max and K m parameter estimates were varied over a 100-fold range. Similar CLr values were predicted for reabsorption models (R1/R2) with variations in V max and K m. Tubular secretion models (S1/S2) yielded similar relationships between Michaelis–Menten parameter perturbations and CLr, but the predicted CLr values were threefold higher for model S1. For both reabsorption and secretion models, the greatest changes in CLr were observed with perturbations in V max, suggesting the need for an accurate estimate of this parameter. When intrinsic clearance was substituted for Michaelis–Menten parameters, it failed to predict similar CLr values even within the linear range. For models S1 and S2, renal secretion was predominant at low doses, whereas renal clearance was driven by fraction unbound in plasma at high doses. Simulations demonstrated the importance of Michaelis–Menten parameter estimates (especially V max) for determining CLr. K m estimates can easily be obtained directly from in vitro studies. However, additional scaling of in vitro V max estimates using in vitro/in vivo extrapolation methods are required to incorporate these parameters into pharmacokinetic models.

KEY WORDS

kidney transport parameters models reabsorption renal clearance secretion 

Notes

ACKNOWLEDGMENTS

This study was supported in part by NIH grant DA-023223 and Roche Inc.

Supplementary material

12248_2012_9437_MOESM1_ESM.docx (36 kb)
ESM 1 (DOCX 36.3 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Melanie A. Felmlee
    • 1
  • Rutwij A. Dave
    • 1
  • Marilyn E. Morris
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, The State University of New YorkBuffaloUSA

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