对乙酰氨基酚
代谢物
药代动力学
葡萄糖醛酸
药理学
基于生理学的药代动力学模型
化学
口服
体内
生物利用度
活性代谢物
医学
生物化学
生物
生物技术
作者
Akiko Toda,Makiko Shimizu,Shotaro Uehara,Takahísa Sasaki,Takahiro Miura,Masayuki Mogi,Masahiro Utoh,Hiroshi Suemizu,Hiroshi Yamazaki
出处
期刊:Xenobiotica
[Informa]
日期:2020-11-19
卷期号:51 (3): 316-323
被引量:4
标识
DOI:10.1080/00498254.2020.1849872
摘要
Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanised-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data.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.Physiologically based pharmacokinetic (PBPK) models (consisting of the 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.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.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.
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