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

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 (ADR alpha 1A, alpha 1B, alpha 1D, alpha 2A, beta 1, beta 2) 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 ADR alpha 1A/B/D, ADR alpha 2A, ADR beta 1 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, beta-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.