Abstract

1. Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanized-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data.

2. Among the animals tested, only rats predominantly converted acetaminophen to sulfate conjugates, rather than glucuronide conjugates. In contrast, the values of area under the plasma concentration curves of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen after oral administration of acetaminophen in marmosets and minipigs were consistent with those reported in humans under the present conditions.

3. Physiologically based pharmacokinetic (PBPK) models (consisting of gut, liver, and central compartments) for acetaminophen and its primary metabolite could reproduce and estimate, respectively, the plasma and hepatic concentrations of acetaminophen in experimental animals and humans after single virtual oral doses.

4. The values of area under the curves of hepatic concentrations of acetaminophen estimated using PBPK models were correlated with the measured levels of cysteinyl acetaminophen (a deactivated metabolite) in plasma fractions in these species.

5. Consequently, using simple PBPK models and plasma data to predict hepatic chemical concentrations after oral doses could be helpful as an indicator of in vivo possible hepatotoxicity of chemicals such as acetaminophen.

摘要

1. 在人源化肝小鼠，对照小鼠，大鼠，普通mar猴，食蟹猴和小型猪中口服10 mg / kg后，通过实验确定对乙酰氨基酚，其葡萄糖醛酸苷和硫酸盐结合物以及半胱氨酰对乙酰氨基酚的血浆浓度；将结果与已报道的人类药代动力学数据进行了比较。

2. 在测试的动物中，只有大鼠主要将对乙酰氨基酚转变为硫酸盐结合物，而不是葡萄糖醛酸化物结合物。相反，在mar猴和小型猪中口服对乙酰氨基酚后，对乙酰氨基酚，其葡糖醛酸和硫酸盐结合物以及半胱氨酰对乙酰氨基酚的血浆浓度曲线下的面积值与当前条件下人类所报道的一致。

3. 对乙酰氨基酚及其主要代谢物的基于生理的药代动力学（PBPK）模型（由肠，肝脏和中央隔室组成）可以在单次虚拟口服剂量后分别重现和估计实验动物和人体内对乙酰氨基酚的血浆和肝脏浓度。

4. 使用PBPK模型估算的肝对乙酰氨基酚浓度曲线下的面积值与这些物种血浆组分中半胱氨酰对乙酰氨基酚（一种失活的代谢产物）的水平相关。

5. 因此，使用简单的PBPK模型和血浆数据来预测口服剂量后的肝脏化学物质浓度可能有助于指示诸如对乙酰氨基酚等化学物质在体内的肝毒性。