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 paracetamol (500 mg/kg) were studied in mice. The correlation between hepatocellular damage and plasma levels of paracetamol metabolites derived from the oxidative pathway were also investigated. Animals were killed at different intervals (1, 2.5 and 6 h) after drug administration. Plasma concentrations of paracetamol and its sulphate, glucuronide, cysteine and mercapturate conjugates were determined by HPLC. Paracetamol plasma levels were significantly higher at 1 and 2.5 h after i.p. administration as compared to oral administration (p = 0.01 and p = 0.02, respectively). Plasma levels of mercapturic acid conjugate were significantly higher at 6 h after i.p. administration (p = 0.04). After 6 h, animals given oral paracetamol showed significantly less necrosis than animals given i.p. paracetamol (p = 0.03). Plasma levels of mercapturate conjugate at 6 h showed a significant correlation with the severity of liver necrosis (r = 0.64; p = 0.02). The results suggest that i.p. paracetamol seems to be more adequate for hepatotoxicity studies in mice.