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<p>The present study predicts effective doses of a set of phenethylamine (PEA) analogues that are frequently present in pre-workout and weight-loss food supplements, to prioritize these compounds for further risk assessment. In vitro determined EC<sub>50</sub> values of PEA analogues for multiple human adrenergic receptor (ADR) subtypes (ADRα<sub>1A</sub>, α<sub>1B</sub>, α<sub>1D</sub>, α<sub>2A</sub>, β<sub>1</sub>, β<sub>2</sub>) and trace-amine associated receptor 1 (TAAR1) were extrapolated to human ED<sub>50</sub> values by using physiologically based kinetic (PBK) modelling-based reverse dosimetry combined with in silico and in vitro determined PBK model input parameters. The predicted ED<sub>50</sub> values of the studied PEAs for activation of ADRα<sub>1A/B/D</sub>, ADRα<sub>2A</sub>, ADRβ<sub>1</sub> and TAAR1 were within a range of 0.914–29.7&#xa0;mg/kg body weight (bw), 139–234&#xa0;mg/kg bw, 0.0839–38.8&#xa0;mg/kg bw and 0.995–264&#xa0;mg/kg bw, respectively. Comparison of the predicted ED<sub>50</sub> values with reported intake values revealed that particularly the exposure of the PEA analogues higenamine, isopropyloctopamine, β-methylphenethylamine and p-synephrine is in the same range or exceeds the predicted ED<sub>50</sub> values. This suggests that these PEAs can (in)directly affect the cardiovascular system after the intake of food supplements. These PEA analogues should therefore be considered as high priority compounds for further risk assessment. In conclusion, our study shows that the use of quantitative in vitro-to-in vivo extrapolation (QIVIVE) of adrenergic and TAAR1 potencies using a generic PBK model can serve as an efficient prioritization method for a whole set of chemical analogues.</p>

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Quantitative in vitro-to-in vivo extrapolation of human adrenergic and trace amine-associated receptor 1 potencies of pre-workout supplement ingredients using physiologically based kinetic modelling-based reverse dosimetry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月3日

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  • Nicole E. T. Pinckaers,
  • W. Matthijs Blankesteijn,
  • Anastasiya Mircheva,
  • Ans Punt,
  • Antoon Opperhuizen,
  • Frederik-Jan van Schooten,
  • Misha Vrolijk

摘要

The present study predicts effective doses of a set of phenethylamine (PEA) analogues that are frequently present in pre-workout and weight-loss food supplements, to prioritize these compounds for further risk assessment. In vitro determined EC50 values of PEA analogues for multiple human adrenergic receptor (ADR) subtypes (ADRα1A, α1B, α1D, α2A, β1, β2) and trace-amine associated receptor 1 (TAAR1) were extrapolated to human ED50 values by using physiologically based kinetic (PBK) modelling-based reverse dosimetry combined with in silico and in vitro determined PBK model input parameters. The predicted ED50 values of the studied PEAs for activation of ADRα1A/B/D, ADRα2A, ADRβ1 and TAAR1 were within a range of 0.914–29.7 mg/kg body weight (bw), 139–234 mg/kg bw, 0.0839–38.8 mg/kg bw and 0.995–264 mg/kg bw, respectively. Comparison of the predicted ED50 values with reported intake values revealed that particularly the exposure of the PEA analogues higenamine, isopropyloctopamine, β-methylphenethylamine and p-synephrine is in the same range or exceeds the predicted ED50 values. This suggests that these PEAs can (in)directly affect the cardiovascular system after the intake of food supplements. These PEA analogues should therefore be considered as high priority compounds for further risk assessment. In conclusion, our study shows that the use of quantitative in vitro-to-in vivo extrapolation (QIVIVE) of adrenergic and TAAR1 potencies using a generic PBK model can serve as an efficient prioritization method for a whole set of chemical analogues.