Details

Autor(en) / Beteiligte

• Noorlander, Annelies
• Wesseling, Sebastiaan
• Rietjens, Ivonne M.C.M.
• van Ravenzwaay, Bennard

Titel

Incorporating renal excretion via the OCT2 transporter in physiologically based kinetic modelling to predict in vivo kinetics of mepiquat in rat

Ist Teil von

• Toxicology letters, 2021-06, Vol.343, p.34-43

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• •This study incorporated active renal excretion via OCT2 of model compound mepiquat in a physiologically based kinetic model.•The RPTEC cell line SA7K is proven to be a step forward in its use as a model to define kinetic parameters Vmax and Km for OCT2 uptake.•Translation of in vitro data to in vivo data is accompanied with usage of adequate scaling factors. 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.