Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, Henan, China.
The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Drug Chem Toxicol. 2019 Nov;42(6):600-607. doi: 10.1080/01480545.2018.1455204. Epub 2018 Apr 12.
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 , 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 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.
氯氮卓（CMZ）单次和多次给药对二乙基亚硝胺（DEN）毒代动力学的影响在正常大鼠和 DEN 诱导的肝纤维化大鼠中进行了研究。12 只大鼠单独用 DEN（50mg/kg）处理，并用腹腔注射（i.p.）CMZ（10、50 或 100mg/kg）单次剂量处理。在多次剂量试验中，6 只大鼠用 CMZ（50mg/kg）治疗 7d，在第 1 天和第 7 天加入 DEN（50mg/kg）。最后，12 只大鼠用 DEN（50mg/kg）通过 i.p.注射每周两次连续 4 周，然后每周注射一次，共 8 周，建立肝纤维化模型。诱导后，这 12 只大鼠给予 CMZ（50mg/kg）联合 DEN（50mg/kg），研究 CMZ 对肝纤维化大鼠 DEN 代谢的抑制作用。还收集并通过验证的高效液相色谱（HPLC）方法分析了连续的血样。单次 CMZ 处理降低了 DEN 清除率（CL），延长了 ，并增加了 DEN 在正常和肝纤维化大鼠中的“曲线下面积”（AUC），而未接受 CMZ 处理的大鼠则没有。用 CMZ 治疗 7d 进一步延长了 DEN 的 ，但与单次 CMZ 治疗相比，CL 和 AUC 没有改变。这些结果表明，CMZ 显著抑制了正常和肝纤维化大鼠 DEN 的代谢。
