Predicting acute paraquat toxicity using physiologically based kinetic modelling incorporating in vitro active renal excretion via the OCT2 transporter

Abstract

Including active renal excretion in physiologically based kinetic (PBK) models can improve their use in quantitative in vitro- in vivo extrapolation (QIVIVE) as a new approach methodology (NAM) for predicting the acute toxicity of organic cation transporter 2 (OCT2) substrates like paraquat (PQ). To realise this NAM, kinetic parameters Vmax and Km for in vitro OCT2 transport of PQ were obtained from the literature. Appropriate scaling factors were applied to translate the in vitro Vmax to an in vivo Vmax. in vitro cytotoxicity data were defined in the rat RLE-6TN and L2 cell lines and the human A549 cell line. The developed PQ PBK model was used to apply reverse dosimetry for QIVIVE translating the in vitro cytotoxicity concentration-response curves to predicted in vivo toxicity dose-response curves after which the lower and upper bound benchmark dose (BMD) for 50% lethality (BMDL₅₀ and BMDU₅₀) were derived by applying BMD analysis. Comparing the predictions to the in vivo reported LD₅₀ values resulted in a conservative prediction for rat and a comparable prediction for human showing proof of principle on the inclusion of active renal excretion and prediction of PQ acute toxicity for the developed NAM.

Keywords: Active renal excretion; Acute toxicity; New approach methodologies (NAM); Paraquat; Physiologically based kinetic (PBK) modeling; Quantitative in vitro- in vivo extrapolation (QIVIVE); Scaling factor.