Metabolic data-dependent physiologically-based kinetic model for cardiotoxicity
2022
Wageningen University, Wageningen, Netherlands
The present study presents an in-vitro-in-silico approach to predict the effect of inter-individual and interethnic 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 25 Caucasian and 25 Chinese human liver microsomes or recombinant cytochrome P450 enzymes, were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations. Ultimately, the maximum concentrations of R- and S-methadone in the heart venous blood of Caucasian and Chinese populations were predicted and the chemical-specific adjustment factor (CSAF) was calculated as a parameter to quantify inter-individual differences in toxicokinetics or toxicodynamics. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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
Miaoying Shi
Added on: 07-26-2022
[1] https://link.springer.com/article/10.1007/s00204-022-03309-y
