Research on the movement of antidotes and toxic metabolites in the patients with acetaminophen poisoning

对乙酰氨基酚被广泛用作止痛和解热药，以代替阿司匹林。由于它包含在市场上的大多数流感药物中，因此很容易获得。人们普遍注意到，相对小剂量的醋氨酚可引起致命的肝损害。对乙酰氨基酚本身无毒，但其中间代谢物N-乙酰基-对苯醌亚胺（NAPQI）已知有毒。NAPQI是一种活性化合物，当还原型谷胱甘肽耗尽时，NAPQI与肝脏中的各种蛋白质不可逆地结合，因此具有肝毒性。质谱，并得到了重要的发现。也就是说，由于NAPQI迅速与活化的SH结合，并且是一种高度不稳定的化合物，因此不可能直接检测到它。然而，我们发现NAPQI与GSH共价键合（GS-APAP）可以相对容易地通过液相色谱/质谱（LCIMS）检测。我们还尝试用LCIMS检测NAC（N-乙酰半胱氨酸），成功地检测到了质谱图的特异性信号，并对因对乙酰氨基酚过量而入院的患者，在入院时和治疗后测定其血药浓度。然而，因药物过量而入院的患者数量太少，而且所有患者的病情都不严重，不足以接受血液净化治疗。因此，我们无法连续测定对乙酰氨基酚及其代谢物的血药浓度变化。我们测定了少数患者灌胃给药解毒剂前后对乙酰氨基酚的血药浓度。

Acetaminophen is widely used as an analgesic and antipyretic drug instead of aspirin. As it is contained in most flu drugs that are on the market, it can easily be obtained. It is widely noticed that a relatively small dose of acetaminophen can cause a fatal hepatic darangement. Acetaminophen itself is not toxic, but its intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI) is known to be toxic. When reduced glutathion, an activated compound, is depleted, NAPQI irreversibly binds with various kinds of protein in the liver, and hence it is hepatotoxic.We investigated to detect the blood concentration of NAPQI with liquid chromatography! mass spectroscopy, and have gotten important findings. That is, asNAPQI promptly combines with activated-SH and is a highly unstable compound, it is impossible to detect it directly. However, we found that NAPQI covalently bond with GSH(GS-APAP) can relatively easily be detected by Liquid Chromatography /Mass Spectrogrphy (LCIMS). We also tried to detect the NAC (N-acetyl-cysteine) with LCIMS, and succeeded to detect the specific signal of mass spectrogram.When patients are admitted due to overdose of acetaminophen, its blood concentrations were determined on admission and after the treatment with antidote. However, the number of patients admitted with the overdose was too small, and all the patients were not severe enough to be treated with blood purification. Hence, we could not determine the changes in the blood concentrations of acetaminophen and its metabolite serially. We determined the blood concentrations of acetaminophen before and after intragastric administration of antidotes in a few patients.