title: In vitro-in vivo extrapolation method to predict human renal clearance of drugs.
abstract: Renal clearance is a key determinant of the elimination of drugs. To date, only few in vitro-in vivo extrapolation (IVIVE) approaches have been described to predict the renal organ clearance as the net result of glomerular filtration, tubular secretion, and tubular reabsorption. In this study, we measured in LLC-PK1 cells the transport of 20 compounds that cover all four classes of the Biopharmaceutical Drug Disposition System. These data were incorporated into a novel kidney model to predict all renal clearance processes in human. We showed that filtration and secretion were main contributors to the renal organ clearance for all compounds, whereas reabsorption was predominant for compounds assigned to classes 1 and 2. Our results suggest that anionic drugs were not significantly secreted in LLC-PK1 cells, resulting in under-predicted clearances. When all study compounds were included a high overall correlation between the reported and predicted renal organ clearances was obtained (R² = 0.83). The prediction accuracy in terms of percentage within twofold and threefold error was 70% and 95%, respectively. In conclusion, our novel IVIVE method allowed to predict the human renal organ clearance and the contribution of each underlying process.
authors.affiliation: Division of Drug Metabolism and Pharmacokinetics, Drug-Drug Interactions Section, Novartis Institutes for BioMedical Research, Basel, CH-4056, Switzerland; Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, CH-4056, Switzerland.
authors.forename: Annett
authors.initials: A
authors.lastname: Kunze
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Birk
authors.initials: B
authors.lastname: Poller
authors.forename: Heike
authors.initials: H
authors.lastname: Gutmann
authors.forename: Gian
authors.initials: G
authors.lastname: Camenisch
mesh_terms: D000042:Absorption; D000465:Algorithms; D000818:Animals; D001692:Biological Transport; D002463:Cell Membrane Permeability; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D018374:LLC-PK1 Cells; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D010599:Pharmacokinetics; D015203:Reproducibility of Results; D013552:Swine
chemical_list: D004364:Pharmaceutical Preparations
keywords: LLC-PK1 cell line; clearance prediction; drug transport; in vitro models; in vitro-in vivo correlations (IVIVC); membrane transport; permeability; pharmacokinetics; renal clearance; renal reabsorption