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In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans

New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R-...

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Autores principales: Shi, Miaoying, Dong, Yumeng, Bouwmeester, Hans, Rietjens, Ivonne M. C. M., Strikwold, Marije
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217890/
https://www.ncbi.nlm.nih.gov/pubmed/35604418
http://dx.doi.org/10.1007/s00204-022-03309-y
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author Shi, Miaoying
Dong, Yumeng
Bouwmeester, Hans
Rietjens, Ivonne M. C. M.
Strikwold, Marije
author_facet Shi, Miaoying
Dong, Yumeng
Bouwmeester, Hans
Rietjens, Ivonne M. C. M.
Strikwold, Marije
author_sort Shi, Miaoying
collection PubMed
description New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03309-y.
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spelling pubmed-92178902022-06-24 In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans Shi, Miaoying Dong, Yumeng Bouwmeester, Hans Rietjens, Ivonne M. C. M. Strikwold, Marije Arch Toxicol Organ Toxicity and Mechanisms New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03309-y. Springer Berlin Heidelberg 2022-05-23 2022 /pmc/articles/PMC9217890/ /pubmed/35604418 http://dx.doi.org/10.1007/s00204-022-03309-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Organ Toxicity and Mechanisms
Shi, Miaoying
Dong, Yumeng
Bouwmeester, Hans
Rietjens, Ivonne M. C. M.
Strikwold, Marije
In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title_full In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title_fullStr In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title_full_unstemmed In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title_short In vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of R- and S-methadone in humans
title_sort in vitro–in silico-based prediction of inter-individual and inter-ethnic variations in the dose-dependent cardiotoxicity of r- and s-methadone in humans
topic Organ Toxicity and Mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9217890/
https://www.ncbi.nlm.nih.gov/pubmed/35604418
http://dx.doi.org/10.1007/s00204-022-03309-y
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