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 (ADRα_1A, α_1B, α_1D, α_2A, 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 ADRα_1A/B/D, ADRα_2A, 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.

Adrenergic receptors; PBK modelling; Phenethylamine analogues; QIVIVE; Trace amine-associated receptor 1.