The Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes, Research Triangle Park, North Carolina, USA.
J Pharmacol Exp Ther. 2012 Aug;342(2):529-40. doi: 10.1124/jpet.112.192930. Epub 2012 May 16.
N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V(max) for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.
N-乙酰半胱氨酸（NAC）是治疗对乙酰氨基酚中毒的首选药物；最常使用的标准 72 小时口服或 21 小时静脉内方案。关于哪种方案是最佳的，以及是否总是需要完整的治疗过程存在争议。在临床试验中解决这些问题具有挑战性。我们使用 DILIsym，一种药物诱导肝损伤的机制模拟，来研究平均患者和样本人群（n = 957）单次过量服用对乙酰氨基酚后的最佳 NAC 治疗方案。对于在摄入后 24 小时内就诊的患者，我们发现口服 NAC 方案比 21 小时静脉内方案保留更多的肝细胞。在各种建模场景中，我们发现 21 小时的 NAC 输注往往太短，而完整的 72 小时口服疗程往往是不必要的。我们发现，达到血清丙氨酸氨基转移酶（ALT）峰值的时间与从肝脏清除 N-乙酰苯醌亚胺（NAPQI）的时间之间通常存在良好的相关性。我们还发现，最常用的治疗列线图低估了在过量摄入后 8 小时内就诊的患者的风险。对乙酰氨基酚生物转化为 NAPQI 的 V（max）是模型中确定个体间易感性差异的最重要变量。总之，DILIsym 预测口服 NAC 治疗方案或相同剂量的静脉内方案优于 21 小时静脉内方案，而 ALT 是停止治疗的最佳可用生物标志物。建模还表明，应考虑修改当前的治疗列线图。
