Inhibitory effect of chlormethiazole on the toxicokinetics of diethylnitrosamine in normal and hepatofibrotic rats.

The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with DEN-induced liver fibrosis. Twelve rats were treated with DEN (50 mg/kg) alone and in combination with a single dose of CMZ (10, 50, or 100 mg/kg) by intraperitoneal (i.p.) injection. In a multiple dose test, six rats were treated with CMZ (50 mg/kg) for 7 d with addition of DEN (50 mg/kg) on days 1 and 7. Lastly, 12 rats were treated with DEN (50 mg/kg) by i.p. injection twice a week for 4 consecutive weeks, followed by weekly injections for another 8 weeks to build the model of liver fibrosis. Following this induction, the 12 rats were given CMZ (50 mg/kg) combined with DEN (50 mg/kg) to study the inhibitory effect of CMZ on DEN metabolism in hepatofibrotic rats. Serial blood samples were also collected and analyzed by a validated high-performance liquid chromatography (HPLC) method. A single-dose CMZ treatment decreased DEN clearance (CL), prolonged the t1/2, and increased the 'area under the curve' (AUC) for DEN in normal and hepatofibrotic rats relative to rats that did not receive CMZ. Treatment with CMZ for 7 d further prolonged the t1/2 for DEN but did not alter the CL and AUC relative to a single CMZ treatment. These results suggest that CMZ significantly inhibits the metabolism of DEN in normal and hepatofibrotic rats.