Population Pharmacokinetic Modeling of Acetaminophen Protein Adducts in Adults and Children.
Population Pharmacokinetic Modeling of Acetaminophen Protein Adducts in Adults and Children.
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DOI：
10.1002/jcph.1555
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发表时间：
2020-05
影响因子：
2.9
通讯作者：
Schmidt S
中科院分区：
文献类型：
--
作者：
Jiang S;Madrasi K;Samant T;Lagishetty C;Vozmediano V;Chiew A;Abdel-Rahman SM;James LP;Schmidt S
对乙酰氨基酚蛋白加合物是一种公认的诊断对乙酰氨基酚毒性的生物标志物。迄今为止，对乙酰氨基酚暴露与加合物暴露之间的定量关系仍有待建立。我们的研究利用群体亲本代谢物模型的方法表征了成人加合物的形成和倾向。它证明了健康受试者的加合物形成有限的药代动力学（PK）。这一发现扩展了现有的关于加合物PK的知识，它显示出明显的长半衰期。然后，我们对儿童进行异速缩放加合物PK模型，模拟加合物的特征，并将这些模拟特征与独立儿童队列中的观察结果进行比较。比例模型在治疗早期明显高估了儿童的加合物浓度，而在重复给药后对乙酰氨基酚的浓度预测不足。这些结果表明，儿童表现出与成人不同的加合物PK行为，很可能是由于儿童的反应性代谢物解毒增加。总之，我们描述了第一个连接对乙酰氨基酚和对乙酰氨基酚蛋白加合物浓度的PK模型，该模型提供了对成人和儿童加合物暴露的不同概况的半机制理解。
Acetaminophen protein adducts (adducts) are a well-established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives the adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent-metabolite modeling. It demonstrated formation-limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long half-life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles to observed ones in an independent cohort of children. The scaled model significantly over-predicted the adduct concentrations in children early on in treatment and under-predicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely due to increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semi-mechanistic understanding of varying profiles of adduct exposure in adults and children.
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DOI：
10.1056/nejmct0708278
发表时间：
2008-07-17
期刊：
The New England journal of medicine
影响因子：
--
作者：
Heard KJ
通讯作者：
Heard KJ
影响因子：
3.9
作者：
James, LP;Mayeux, PR;Hinson, JA
通讯作者：
Hinson, JA
DOI：
10.1111/j.1365-2125.1984.tb02495.x
发表时间：
1984-01-01
影响因子：
3.4
作者：
CLEMENTS, JA;CRITCHLEY, JAJH;PRESCOTT, LF
通讯作者：
PRESCOTT, LF
DOI：
10.1124/jpet.102.053124
发表时间：
2003-10-01
影响因子：
3.5
作者：
Johnsrud, EK;Koukouritaki, SB;McCarver, DG
通讯作者：
McCarver, DG
影响因子：
2.9
作者：
James, Laura P.;Chiew, Angela;Roberts, Dean
通讯作者：
Roberts, Dean