Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT greater than 500 mu/l) and severe on 5 (ALT less than 1000 mu/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg.h.l-1, 2.91 h and 3.18 ml.min-1.kg-1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.

This is the first study documenting placental transfer of N-acetylcysteine in humans and provides impetus for research establishing a direct antidotal effect of N-acetylcysteine in the fetus.

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1 Paraquat can be removed by haemodialysis and haemoperfusion but, although clearance values are high, the quantities recovered are insignificant. Prevention of death is most unlikely except perhaps in patients with plasma paraquat concentrations very close to the previously proposed line separating concentrations in fatal cases and survivors at different time intervals. 2 Even if delays incurred in measuring plasma paraquat concentrations and in setting up haemodialysis or haemoperfusion could be reduced to a minimum, elimination by these procedures would achieve little because paraquat disappears rapidly from the plasma in the first few hours after ingestion as it is taken up by the tissues and excreted into the urine. 3 Further studies on patients at borderline risk are required and the value of 'continuous' haemoperfusion requires further assessment.

A rapid method was developed for the estimation of colchicine in plasma. The method was used to determine colchicine levels in a fatal case of colchicine self-poisoning.

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