Wu Jhy-Wen, Tsai Tung-Hu
National Yang-Ming University, School of Medicine, Institute of Traditional Medicine, 155, Li-Nong Street Section 2, Taipei 112, Taiwan.
Drug Metab Dispos. 2007 Sep;35(9):1603-10. doi: 10.1124/dmd.107.014894. Epub 2007 May 31.
Pyrazinamide (PZA) is widely used in combination with other drugs in chemotherapy for tuberculosis. However, the dose-related liver injury is the main adverse effect of PZA and its metabolite [pyrazinoic acid (PA)]. Silibinin is the main flavonoid extracted from milk thistle (Silybum marianum), and it displays hepatoprotective properties. This study investigates the pharmacokinetics of PZA and PA and their interaction with silibinin in rats. The parallel study design was divided into six groups: PZA alone, PZA + long-term silibinin exposure, PZA + concomitant short-term silibinin exposure, PA alone, PA + long-term silibinin exposure, and PA + concomitant short-term silibinin exposure groups. The results indicate that the distribution ratio of PZA from bile to blood [area under the curve (AUC)(bile)/AUC(blood)] in the PZA + long-term silibinin exposure and PZA + concomitant short-term silibinin exposure groups was also not significantly different when compared with the PZA alone group. However, the bile-to-blood distribution ratio of PA was significantly decreased in the PA + long-term silibinin exposure and the PA + concomitant short-term silibinin exposure groups. On PZA administration, the blood, but not bile, levels of PA were markedly increased in the PZA + long-term silibinin exposure and PZA + concomitant short-term silibinin exposure groups, but the bile-to-blood ratio of PA was decreased. These results suggest that the excretion pathway of PA may be blocked by silibinin through xanthine oxidase and hepatobiliary excretion.
吡嗪酰胺（PZA）在结核病化疗中广泛与其他药物联合使用。然而，与剂量相关的肝损伤是PZA及其代谢产物[吡嗪酸（PA）]的主要不良反应。水飞蓟宾是从水飞蓟（Silybum marianum）中提取的主要黄酮类化合物，具有肝脏保护特性。本研究调查了PZA和PA在大鼠体内的药代动力学及其与水飞蓟宾的相互作用。平行研究设计分为六组：单独使用PZA组、PZA + 长期水飞蓟宾暴露组、PZA + 短期水飞蓟宾同时暴露组、单独使用PA组、PA + 长期水飞蓟宾暴露组和PA + 短期水飞蓟宾同时暴露组。结果表明，与单独使用PZA组相比，PZA + 长期水飞蓟宾暴露组和PZA + 短期水飞蓟宾同时暴露组中PZA从胆汁到血液的分布比率[曲线下面积（AUC）（胆汁）/AUC（血液）]也无显著差异。然而，在PA + 长期水飞蓟宾暴露组和PA + 短期水飞蓟宾同时暴露组中，PA的胆汁 - 血液分布比率显著降低。给予PZA后，PZA + 长期水飞蓟宾暴露组和PZA + 短期水飞蓟宾同时暴露组中PA的血液水平显著升高，但胆汁中PA水平未升高，且PA的胆汁 - 血液比率降低。这些结果表明，水飞蓟宾可能通过黄嘌呤氧化酶和肝胆排泄途径阻断PA的排泄。
