Alteration of Methotrexate Biliary and Renal Elimination during Extrahepatic and Intrahepatic Cholestasis in Rats
Alteration of Methotrexate Biliary and Renal Elimination during Extrahepatic and Intrahepatic Cholestasis in Rats
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DOI：
10.1248/bpb.32.1978
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发表时间：
2009-12-01
影响因子：
2
通讯作者：
Micuda, Stanislav
中科院分区：
文献类型：
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作者：
Brcakova, Eva;Fuksa, Leos;Micuda, Stanislav
甲氨蝶呤（MTX）是一种重要的抗肿瘤和免疫抑制剂，已被建议用于治疗原发性胆汁性肝硬化。然而，药物的药效学和毒性取决于其在血浆中的浓度，而血浆中的浓度又与MTX在肝脏和肾脏中的消除直接相关。因此，本研究的目的是评估MTX胆汁和肾脏排泄的变化，无论是在肝内或梗阻性胆汁淤积大鼠。在大鼠胆道梗阻（BDO）后1天（BDO 1）、7天（BDO 7）及内毒素（LPS）给药后18小时，测定MTX的稳态药代动力学参数。与相应的对照组相比，BDO 1组中混合物的胆汁和总清除率分别降低至12%和49%，BDO 7组动物分别降低至5%和56%，LPS组分别降低至42%和43%。MTX的肾清除率在BDO组中没有变化，但在LPS动物中降低至对照组的23%。血清生化和主要肝MTX转运体（Mrp2、Mrp3、Mrp4、Bcrp、Oatp1a1、Oatp1a4和Oatp1b2）的表达证实了肝中的病理性胆汁淤积改变，并部分阐明了MTX药代动力学参数变化的原因。总之，本研究是第一个描述显着改变甲氨蝶呤肝脏和肾脏消除引起的胆汁淤积在大鼠。此外，报告的MTX药代动力学和各自的转运蛋白表达的变化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。
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 stead), 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 mix 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.