LIVER-DAMAGE AND PLASMA-CONCENTRATIONS OF PARACETAMOL AND ITS METABOLITES AFTER PARACETAMOL OVERDOSAGE IN MICE

The effects of single oral and intraperitoneal (i.p.) overdoses of par acetamol (500 mg/kg) were studied in mice. The correlation between hep atocellular damage and plasma levels of paracetamol metabolites derive d from the oxidative pathway were also investigated. Animals were kill ed at different intervals (1, 2.5 and 6 h) after drug administration. Plasma concentrations of paracetamol and its sulphate, glucuronide, cy steine and mercapturate conjugates were determined by HPLC. Paracetamo l plasma levels were significantly higher at 1 and 2.5 h after i.p. ad ministration as compared to oral administration (p = 0.01 and p = 0.02 , respectively). Plasma levels of mercapturic acid conjugate were sign ificantly higher at 6 h after i.p. administration (p = 0.04). After 6 h, animals given oral paracetamol showed significantly less necrosis t han animals given ip. paracetamol (p = 0.03). Plasma levels of mercapt urate conjugate at 6 h showed a significant correlation with the sever ity of liver necrosis (r = 0.64; p = 0.02). The results suggest that i .p. paracetamol seems to be more adequate for hepatotoxicity studies i n mice.