Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague.
Biol Pharm Bull. 2009 Dec;32(12):1978-85. doi: 10.1248/bpb.32.1978.
Methotrexate (MTX), an important anticancer and immunosuppressive agent, has been suggested for the treatment of primary biliary cirrhosis. However, the drug's pharmacodynamics and toxicity is dependent on its concentrations in plasma which in turn are directly related to MTX's elimination in the liver and kidney. Therefore, the aim of this study was to evaluate changes in MTX biliary and renal excretion during either intrahepatic or obstructive cholestasis in rats. The steady state pharmacokinetic parameters of MTX were evaluated in rats one (BDO1) or seven (BDO7) days after bile duct obstruction (BDO) or 18 h after administration of lipopolysaccharide (LPS). In comparison to the respective control groups, biliary and total clearances of MTX were decreased to 12% and 49% in the BDO1 group, to 5% and 56% in the BDO7 animals, and to 42% and 43% in the LPS group, respectively. Renal clearance of MTX was unchanged in BDO groups, but decreased to 23% of controls in the LPS animals. The serum biochemistry and expression of main hepatic MTX transporters (Mrp2, Mrp3, Mrp4, Bcrp, Oatp1a1, Oatp1a4 and Oatp1b2) confirmed the pathological cholestatic changes in the liver and partly elucidated the cause of changes in MTX pharmacokinetic parameters. In conclusion, this study is the first describing marked alteration of MTX hepatic and renal elimination induced by cholestasis in rats. Moreover, the reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models.
甲氨蝶呤（MTX）是一种重要的抗癌和免疫抑制剂，已被提议用于原发性胆汁性肝硬化的治疗。然而，该药物的药效学和毒性取决于其在血浆中的浓度，而血浆浓度又直接与 MTX 在肝脏和肾脏中的消除有关。因此，本研究旨在评估在大鼠肝内或阻塞性胆汁淤积期间 MTX 胆汁和肾排泄的变化。在胆管阻塞（BDO）后 1 天（BDO1）或 7 天（BDO7）或给予脂多糖（LPS）后 18 小时，评估 MTX 的稳态药代动力学参数。与各自的对照组相比，BDO1 组 MTX 的胆汁和总清除率分别下降到 12%和 49%，BDO7 组下降到 5%和 56%，LPS 组下降到 42%和 43%。BDO 组 MTX 的肾清除率不变，但 LPS 组下降到对照组的 23%。血清生化和主要肝 MTX 转运体（Mrp2、Mrp3、Mrp4、Bcrp、Oatp1a1、Oatp1a4 和 Oatp1b2）的表达证实了肝脏的病理性胆汁淤积变化，并部分阐明了 MTX 药代动力学参数变化的原因。总之，本研究首次描述了 MTX 在大鼠胆汁淤积时肝和肾清除的明显改变。此外，报告的 MTX 药代动力学变化和各自的转运体表达表明，两种广泛使用的胆汁淤积模型之间存在重要的机制差异。
