Incorporating renal excretion via the OCT2 transporter in physiologically based kinetic modelling to predict in vivo kinetics of mepiquat in rat
| Autor: | Ivonne M.C.M. Rietjens, Bennard van Ravenzwaay, Annelies Noorlander, Sebastiaan Wesseling |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Active renal excretion Kidney Toxicology Models Biological Mepiquat Cell Line Physiologically based kinetic modeling Kidney Tubules Proximal Excretion 03 medical and health sciences 0302 clinical medicine Piperidines Plant Growth Regulators In vivo Organic cation transporter 2 medicine Animals Humans Scaling factor In vivo kinetics Toxicologie VLAG WIMEK Chemistry ORGANIC CATION TRANSPORTER 2 Epithelial Cells Transporter IT Development General Medicine In vitro Epithelium Rats 030104 developmental biology medicine.anatomical_structure Renal physiology Biophysics Renal proximal tubule epithelial cell line 030217 neurology & neurosurgery |
| Zdroj: | Toxicology Letters 343 (2021) Toxicology Letters, 343, 34-43 |
| ISSN: | 0378-4274 |
| Popis: | The present study aimed at incorporating active renal excretion via the organic cation transporter 2 (OCT2) into a generic rat physiologically based kinetic (PBK) model using an in vitro human renal proximal tubular epithelial cell line (SA7K) and mepiquat chloride (MQ) as the model compound. The Vmax (10.5 pmol/min/mg protein) and Km (20.6 μM) of OCT2 transport of MQ were determined by concentration-dependent uptake in SA7K cells using doxepin as inhibitor. PBK model predictions incorporating these values in the PBK model were 6.7-8.4-fold different from the reported in vivo data on the blood concentration of MQ in rat. Applying an overall scaling factor that also corrects for potential differences in OCT2 activity in the SA7K cells and in vivo kidney cortex and species differences resulted in adequate predictions for in vivo kinetics of MQ in rat (2.3-3.2-fold). The results indicate that using SA7K cells to define PBK parameters for active renal OCT2 mediated excretion with adequate scaling enables incorporation of renal excretion via the OCT2 transporter in PBK modelling to predict in vivo kinetics of mepiquat in rat. This study demonstrates a proof-of-principle on how to include active renal excretion into generic PBK models. |
| Databáze: | OpenAIRE |
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