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

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

doi:10.1016/j.toxlet.2021.02.013

Annelies Noorlander, Sebastiaan Wesseling + Show 2 more

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https://doi.org/10.1016/j.toxlet.2021.02.013

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Abstract

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.

Highlights

Based kinetic (PBK) modelling-facilitated reverse dosimetry is a useful tool for quantitative in vitro-in vivo extrapolation (QIVIVE) to predict in vivo toxicity (Louisse et al., Abbreviations: Physiologically based kinetic (PBK), physiologically based kinetic modelling; QIVIVE, quantitative in vitro-in vivo extrapolation; RPTEC, renal proximal tubule epithelial cells; OCT2, organic cation transporter 2; mepiquat chloride (MQ), mepiquat; SA7K, generated human renal proximal tubule epithelial cell line; MATE, multidrug and toxin extrusion transporter; PBS, phosphate buffered saline; BSA, bovine serum albumin.2017; Zhang et al, 2018)
This confirms that MQ uses an organic cationic transport system, OCT2, to be taken up from the medium into the SA7K cells, which represents the first step in its active elimination via the kidneys
Our study aimed at incorporating renal active excretion into PBK modelling using the RPTEC cell line SA7K to determine the values of kinetic parameters Vmax and Km for OCT2 transport of the model compound MQ

Summary

Introduction

Based kinetic (PBK) modelling-facilitated reverse dosimetry is a useful tool for quantitative in vitro-in vivo extrapolation (QIVIVE) to predict in vivo toxicity (Louisse et al., Abbreviations: PBK, physiologically based kinetic modelling; QIVIVE, quantitative in vitro-in vivo extrapolation; RPTEC, renal proximal tubule epithelial cells; OCT2, organic cation transporter 2; MQ, mepiquat; SA7K, generated human renal proximal tubule epithelial cell line; MATE, multidrug and toxin extrusion transporter; PBS, phosphate buffered saline; BSA, bovine serum albumin.2017; Zhang et al, 2018). Proofs-of-principle for QIVIVE based on PBK modelling facilitated reverse dosimetry have been provided for a number of adverse outcomes including liver toxicity (Ning et al, 2019), kidney toxicity (Abdullah et al, 2016), developmental toxicity (Louisse et al, 2015; Strikwold et al, 2017) and cardiotoxicity (Shi et al, 2020). These examples, did not relate to model compounds for which plasma and tissue concentrations depend on kinetics for excretion.

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