College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea.
J Toxicol Environ Health A. 2009;72(21-22):1395-405. doi: 10.1080/15287390903212741.
The objectives of this study were to (1) develop physiologically based pharmacokinetic (PBPK) models for zearalenone following intravenous (i.v.) and oral (p.o.) dosing in rats and (2) predict concentrations in humans via interspecies scaling. The model for i.v. 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 p.o. 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 i.v. or p.o. administration. Upon model validation in rats, steady-state zearalenone concentrations in blood and tissues were simulated for rats after once daily p.o. 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 p.o. 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 p.o. 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 p,o, exposure conditions.
（1）建立基于生理学的玉米赤霉烯酮静脉（i.v.）和口服（p.o.）给药在大鼠体内的药代动力学（PBPK）模型；（2）通过种间缩放预测人体浓度。静脉给药模型包括静脉、动脉、肺、肝、脾、肾、心、睾丸、脑、肌肉、脂肪组织、胃和小肠。为了描述口服给药后观察到的双峰现象，构建了吸收模型以反映葡萄糖醛酸化、胆汁排泄、肠肝循环以及腔室中快速和缓慢的吸收过程。所开发的模型能够充分描述静脉或口服给药后大鼠的观察到的浓度-时间数据。在大鼠模型验证后，模拟了大鼠每日口服暴露（0.1 mg/kg/d）后血液和组织中的稳态玉米赤霉烯酮浓度。预测的大鼠稳态血液玉米赤霉烯酮浓度平均值为 0.014 ng/ml。随后，确定了每日口服人类剂量，以达到在大鼠中发现的相同稳态血液浓度（0.014 ng/ml），即 0.0312 mg/kg/d 或 2.18 mg/70 kg/d。还模拟了多次口服给药后血液和组织中人类的稳态玉米赤霉烯酮浓度-时间曲线（剂量 0.0312 mg/kg/d）。所开发的 PBPK 模型能够充分描述大鼠的药代动力学特征，并且可能有助于预测不同 p,o 暴露条件下人类血液和组织中玉米赤霉烯酮的浓度。
