Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study
- 567 Downloads
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 WORDSkidney transport parameters models reabsorption renal clearance secretion
This study was supported in part by NIH grant DA-023223 and Roche Inc.
- 14.Watanabe T, Kusuhara H, Debori Y, Maeda K, Kondo T, Nakayama H, et al. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug–drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos Biol Fate Chem. 2011;39(6):1031–8. Epub 2011/03/09.PubMedCrossRefGoogle Scholar
- 23.Itagaki S, Shimamoto S, Hirano T, Iseki K, Sugawara M, Nishimura S, et al. Comparison of urinary excretion of phenolsulfonphthalein in an animal model for Wilson’s disease (Long-Evans Cinnamon rats) with that in normal Wistar rats: involvement of primary active organic anion transporter. J Pharm Pharm Sci Publ Can Soc Pharm Sci, Soc Can Sci Pharm. 2004;7(2):227–34. Epub 2004/09/16.Google Scholar
- 27.Tahara H, Kusuhara H, Chida M, Fuse E, Sugiyama Y. Is the monkey an appropriate animal model to examine drug–drug interactions involving renal clearance? Effect of probenecid on the renal elimination of H2 receptor antagonists. J Pharmacol Exp Ther. 2006;316(3):1187–94. Epub 2005/11/18.PubMedCrossRefGoogle Scholar