The role of cytochrome-P450 inhibitors in the prevention of hepatotoxicity after paracetamol overdose in rats.

Despite the understanding that some cytochrome P450 isoforms are responsible for activation of paracetamol to the hepatotoxic metabolite, N-acetyl-p-benzoquinineimine (NAPQI), the use of enzyme inhibitors for prevention and/or treatment of paracetamol hepatotoxicity is still not well researched. Here, a mixture of ketoconazole, isoniazid and caffeine (inhibitor solution), known inhibitors of CYP3A, CYP2E1 and CYP1A2, was investigated for prevention of hepatotoxicity after paracetamol over-dose in rats. The appropriate doses of paracetamol (1000 mg/kg/day) and the 'inhibitor solution' (ketoconazole 5 mg/kg, isoniazid 5 mg/kg and caffeine 10 mg/kg; =KIC-5-50), were selected in preliminary experiments. Thereafter, two groups of 15 male Sprague-Dawley rats each were treated with the toxic dose of paracetamol intraperitoneally to induce severe hepatotoxicity. But one of the two groups was treated with the KIC-5-50 intraperitoneally 5 min after administration of paracetamol. Five rats were killed at 24, 48 and 72 hours after paracetamol administration. Plasma concentrations of paracetamol were determined by the polarization fluorescent immunoassay and a piece of liver was sent for histopathology examination. Liver function tests at 48 hours were higher in the 'paracetamol only' treated group than in the 'KIC-5-50 + paracetamol' treated group' (P < 0.05), i.e., median (range) AST 2025 (530-4329) i.u./L, ALT 1174 (662-2395) i.u./L versus AST 194 (81-494) i.u./L, ALT 311 (201-945) i.u./L, respectively. The corresponding plasma concentrations of paracetamol were 0.26 (0.13-1.02) microg/mL for the 'paracetamol only' treated group versus 0.17 (0.07-0.33) microg/ml for the 'KIC-5-50 + paracetamol' treated group. Centrilobular necrosis, the pathogmonomic feature of paracetamol hepatotoxicity, was demonstrated only in the 'paracetamol only' treated group. In conclusion, coadministration of paracetamol with inhibitors of cytochrome P450 prevented the development of paracetamol-induced hepatotoxicity in rats, and this calls for research for enzyme inhibitors that may be of therapeutic value.