Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

Boonpawa, Rungnapa; Spenkelink, A.; Punt, Ans; Rietjens, Ivonne M.C.M.

doi:10.1002/mnfr.201600894

Cited by 30 publications

(26 citation statements)

References 52 publications

(130 reference statements)

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“…To overcome this issue, alternative testing strategies can be considered, including physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry (Louisse et al 2017 ) that enables quantitative in vitro to in vivo extrapolation (QIVIVE), as a potential novel approach in risk assessment. The PBK modelling-based alternative approach has been successfully used to predict chlorpyrifos-related AChE inhibition (Timchalk et al 2002 ; Zhao et al 2019 ) and also a variety of other chemical-induced adverse effects including for example cardiotoxicity induced by methadone, liver toxicity induced by pyrrolizidine alkaloids and developmental toxicity of retinoids, glycolethers and phenols (Boonpawa et al 2017 ; Louisse et al 2010 ; Ning et al 2019 ; Shi et al 2020 ; Strikwold et al 2013 , 2017 ). In case of DZN, previously a physiologically based pharmacokinetic and pharmacodynamic model was developed for both human and rat (Poet et al 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

et al. 2021

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The present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.

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Section: Introductionmentioning

confidence: 99%

Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

et al. 2021

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“…Berkeley Madonna 8.3.18 (Macey and Oster, UC Berkeley, CA) was used to code and numerically integrate the PBK models applying Rosenbrock's algorithm for stiff systems. Compared to other algorithms in Berkeley Madonna (BM), the Rosenbrock's algorithm serves better for stiff systems and was shown to provide adequate results in previous studies providing proofs of principle for the PBK model based reverse dosimetry …”

Section: Methodsmentioning

confidence: 99%

Combining In Vitro Data and Physiologically Based Kinetic Modeling Facilitates Reverse Dosimetry to Define In Vivo Dose–Response Curves for Bixin‐ and Crocetin‐Induced Activation of PPARγ in Humans

Suparmi

Haan

Spenkelink

et al. 2020

Molecular Nutrition Food Res

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Scope: It is investigated whether at realistic dietary intake bixin and crocetin could induce peroxisome proliferator-activated receptor (PPAR )-mediated gene expression in humans using a combined in vitro-in silico approach. Methods and results: Concentration-response curves obtained from in vitro PPAR -reporter gene assays are converted to in vivo dose-response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD 50 ) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPAR -mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD 50 values for in vivo PPAR activation are about 30-fold different, amounting to 115 and 3505 mg kg bw −1 for crocetin and bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD 50 values for crocetin but not for bixin, pointing at better possibilities for in vivo PPAR activation by crocetin. Conclusion: Based on a combined in vitro-in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of bixin and crocetin are likely to reach concentrations that activate PPAR -mediated gene expression, without the need for a human intervention study.

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“…This activity is known as quantitative in vitro to in vivo extrapolation (QIVIVE) ( Bale et al, 2014 ; Hartung, 2017 ). Examples of QIVIVE increasingly involve the application of physiologically based kinetic (PBK) modeling–based reverse dosimetry for the translation of in vitro to in vivo responses and the derivation of in vivo BMDs ( Adam et al, 2019 ; Boonpawa et al, 2017 ; Li et al, 2017 ; Louisse et al, 2016 ; Louisse et al, 2010 ; Louisse et al, 2012 ; Punt et al, 2017 ; Shi et al, 2020 ; Strikwold et al, 2017a ; Strikwold et al, 2013 ; Strikwold et al, 2017b ; Zhang et al, 2020 ; Zhao et al, 2019 ). Within this approach, all parameters, other than input dose or exposure, are held fixed at central values.…”

Section: Introductionmentioning

confidence: 99%

Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration–Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

et al. 2021

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A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for perfluorooctanoic acid (PFOA) and high throughput screening (HTS) in vitro concentration–response data, determined in a human liver cell line, from the ToxCast/Tox21 database. In vivo benchmark doses (BMDs) for PFOA intake (ng/kg BW/day) and drinking water exposure concentrations (µg/L) were calculated from the in vivo dose responses and compared to intake values derived by the European Food Safety Authority (EFSA). The intake benchmark dose lower confidence limit (BMDL5) of 0.82 was similar to 0.86 ng/kg BW/day for altered serum cholesterol levels derived by EFSA, whereas the intake BMDL5 of 6.88 was six-fold higher than the value of 1.14 ng/kg BW/day for altered antibody titer also derived by the EFSA. Application of a chemical-specific adjustment factor (CSAF) of 1.4, allowing for inter-individual variability in kinetics, based on biological half-life, gave an intake BMDL5 of 0.59 for serum cholesterol and 4.91 (ng/kg BW/day), for decreased antibody titer, which were 0.69 and 4.31 the EFSA-derived values, respectively. The corresponding BMDL5 for drinking water concentrations, for estrogen receptor binding activation associated with breast cancer, pregnane X receptor binding associated with altered serum cholesterol levels, thyroid hormone receptor α binding leading to thyroid disease, and decreased antibody titer (pro-inflammation from cytokines) were 0.883, 0.139, 0.086, and 0.295 ng/ml, respectively, with application of no uncertainty factors. These concentrations are 5.7-, 36-, 58.5-, and 16.9-fold lower than the median measured drinking water level for the general US population which is approximately, 5 ng/ml.

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Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

Abstract: The developed PBK model adequately predicts absorption, distribution, metabolism, and excretion of hesperidin in humans and allows to evaluate the human in vivo situation without the need for human intervention studies.

Cited by 30 publications

References 52 publications

Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

Combining In Vitro Data and Physiologically Based Kinetic Modeling Facilitates Reverse Dosimetry to Define In Vivo Dose–Response Curves for Bixin‐ and Crocetin‐Induced Activation of PPARγ in Humans

Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration–Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

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