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

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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.