长期饮酒或低谷胱甘肽的成年人在过量使用缓释和速释制剂后对乙酰氨基酚药代动力学和肝脏生物标志物的定量系统毒理学建模

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Kyunghee Yang, James J Beaudoin, Brett A Howell, James Mullin, Elham Amini, John C K Lai, Cathy K Gelotte, Sury Sista, Evren Atillasoy
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引用次数: 0

摘要

对乙酰氨基酚(APAP)是一种非处方止痛药和解热药,当摄入大量过量时可引起肝毒性。APAP有多种制剂,包括速释制剂(IR)和缓释制剂(ER)。最近发表的一份关于APAP中毒管理的共识声明表明,APAP- er过量的管理与APAP- ir过量的管理相同。与这一共识一致,之前有报道称,使用DILIsym的定量系统毒理学(QST)模型预测了健康成人过量服用APAP-ER和APAP-IR制剂的相似药代动力学(PK)和肝脏生物标志物谱。APAP的肝损伤是由反应性代谢物n -乙酰-ρ-苯醌亚胺(NAPQI)引起的,NAPQI主要由cyp2e1介导的代谢形成,并被肝谷胱甘肽消除。因此,过量使用APAP-IR和APAP-ER后,可以增加NAPQI生成(如酒精诱导CYP2E1)或减少肝脏谷胱甘肽储存(如潜在肝病)的条件可能会影响PK和对肝毒性的易感性。本研究在DILIsym中建立并验证了慢性酒精使用者和低肝谷胱甘肽个体的APAP-IR和APAP-ER模型。使用经过验证的模型进行模拟,预测中度和过量慢性酒精使用者以及肝谷胱甘肽水平低的成年人在单次急性过量服用(高达100 g)和重复超治疗摄入(高达7.8 g/天,持续10天)后,APAP-ER和APAP-IR配方的PK和肝脏生物标志物谱相似。这些结果进一步支持管理APAP-IR过量的方法可以应用于管理慢性饮酒或肝谷胱甘肽水平较低的成人APAP-ER过量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Quantitative Systems Toxicology Modeling of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Adults With Chronic Alcohol Use or Low Glutathione.

Acetaminophen (APAP), an over-the-counter analgesic and antipyretic, can cause hepatotoxicity when ingested in large overdoses. APAP has multiple formulations including immediate-release (IR) and extended-release (ER) preparations. A recently published consensus statement on the management of APAP poisoning indicated that management of APAP-ER overdose is the same as that for APAP-IR overdose. Consistent with this consensus, it was previously reported that quantitative systems toxicology (QST) modeling using DILIsym predicted similar pharmacokinetic (PK) and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations after overdose in healthy adults. Hepatic injury from APAP is caused by the reactive metabolite, N-acetyl-ρ-benzoquinone imine (NAPQI), which is formed predominantly by CYP2E1-mediated metabolism and eliminated by hepatic glutathione. As such, conditions that can increase NAPQI production (e.g., CYP2E1 induction by alcohol) or decrease hepatic glutathione stores (e.g., underling liver disease) may impact PK and susceptibility to hepatotoxicity after overdose of APAP-IR and APAP-ER. In the current study, APAP-IR and APAP-ER models in chronic alcohol users and individuals with low hepatic glutathione were developed and verified within DILIsym. Simulations using verified models predicted similar PK and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations in moderate and excessive chronic alcohol users and adults with low hepatic glutathione levels after single acute overdoses up to ~100 g and repeat supratherapeutic ingestions (up to 7.8 g/day for 10 days). These results further support that approaches to manage APAP-IR overdoses can be applied to manage APAP-ER overdoses in adults with chronic alcohol consumption or lower hepatic glutathione levels.

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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