Physiologically based pharmacokinetics of zearalenone

The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (iv) and oral (po) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for iv dosing consisted of vein, artery, lung, liver, spleen, kidneys, heart, testes, brain, muscle, adipose tissue, stomach, and small intestine. To describe the secondary peak phenomenon observed after po administration, the absorption model was constructed to reflect glucuronidation, biliary excretion, enterohepatic recirculation, and fast and slow absorption processes from the lumenal compartment. The developed models adequately described observed concentration-time data in rats after iv or po administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily po exposures (0.1 mg/kg/d). The average steady-state blood zearalenone concentration predicted in rat was 0.014 ng/ml. Subsequently, a daily human po dose needed to achieve the same steady-state blood concentration found in rats (0.014 ng/ml) was determined to be 0.0312 mg/kg/d or 2.18 mg/70 kg/d. The steady-state zearalenone concentration-time profiles in blood and tissues were also simulated for human after multiple po administrations (dose 0.0312 mg/kg/d). The developed PBPK models adequately described the pharmacokinetics in rats and may be useful in predicting human blood and tissue concentrations for zearalenone under different po exposure conditions.