Effects of ethanol ingestion on the metabolism of a hepatotoxic dose of paracetamol in mice.

After administration to mice of a hepatotoxic dose of paracetamol (400 mg/kg body wt, p.o.) peak plasma concentrations of the drug and its glucuronide were approximately 900 microM around one hour. Corresponding levels of the sulphate, mercapturate and cysteine conjugates were approximately 100, 35 and 20 microM, respectively. Urinary excretion accounted for 55% of the administered drug 31 h after dosing. Of this total, 64.7% was paracetamol glucuronide, 17.9% paracetamol cysteine, 10.4% paracetamol sulphate, 0.5% paracetamol mercapturate and 6.5% unchanged drug. One hour after acute ethanol administration (3 g/kg, p.o., concomitantly with paracetamol) plasma levels of the glucuronide, cysteine and mercapturate conjugates were decreased by approximately 50%. There were reductions in the urinary excretion of the glucuronide (-13%) and cysteine conjugates (-24%), but increases in the amounts of mercapturate (+52%), sulphate +11%) and unchanged drug (+81%). Chronic ethanol ingestion (15 g/kg per d for 28 d) caused a transient initial increase in plasma paracetamol cysteine (+32%) and mercapturate (+41%) concentrations, but the only substantial change in urinary excretion was a 29% increase in the amount of paracetamol glucuronide. After chronic ethanol consumption, acute ethanol administration had a transient inhibitory effect on paracetamol mono-oxygenation, but glucuronidation was unaffected (as judged by plasma concentrations). Only paracetamol mercapturate excretion was substantially affected (+64%).