Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Simkova 870, 50038 Hradec Kralove, Czech Republic.
Toxicology. 2010 Jan 12;267(1-3):165-71. doi: 10.1016/j.tox.2009.11.010. Epub 2009 Nov 14.
Increased hepatotoxicity of methotrexate has been reported during dexamethasone therapy in humans. Despite the observed inducing effect of dexamethasone on some methotrexate transporting proteins in the liver, the kinetic aspects of this interaction have not been studied yet. Thus, the aim of the present study was to evaluate the influence of dexamethasone on the hepatic and overall pharmacokinetics of methotrexate. Pharmacokinetics of methotrexate was evaluated in rats during an in vivo steady-state clearance study after either single intravenous dose of dexamethasone or its four-day oral administration in a dose optimized for transport proteins induction. Dexamethasone oral pretreatment reduced biliary clearance of methotrexate by 53%. Although liver tissue concentration of methotrexate increased only slightly in these animals, a significant increase in liver weights produced by dexamethasone pretreatment revealed a marked increase in liver content of the drug. An evaluation of plasma liver enzyme activities measured before and after methotrexate administration demonstrated a potentiation of corticosteroid hepatotoxicity by the cytostatic. Analysis of methotrexate transporter expression in the liver showed up-regulation of Mrp2, Oatp1a4, and Oat2, and down-regulation of Mrp3. These observations comply with increased biliary excretion and reduced plasma concentrations of their endogenous substrate, conjugated bilirubin. In contrast, single intravenous bolus of dexamethasone did not influence any pharmacokinetic parameter of methotrexate. In conclusion, these results indicate that hepatocellular impairment associated with reduced biliary elimination of methotrexate, and its raised liver content may contribute to increased hepatotoxicity of the drug when co-administered with dexamethasone. Moreover, an influence of dexamethasone on protein expression of anionic drugs transporters in the liver and kidney was demonstrated.
在人类中，地塞米松治疗期间已报道甲氨蝶呤的肝毒性增加。尽管观察到地塞米松对肝脏中的某些甲氨蝶呤转运蛋白具有诱导作用，但尚未研究这种相互作用的动力学方面。因此，本研究的目的是评估地塞米松对甲氨蝶呤的肝内和总体药代动力学的影响。在单次静脉注射地塞米松或优化用于诱导转运蛋白的四天口服给药后的体内稳态清除研究中，评估了甲氨蝶呤在大鼠中的药代动力学。地塞米松口服预处理使甲氨蝶呤的胆汁清除率降低了 53％。尽管这些动物的肝组织中甲氨蝶呤浓度仅略有增加，但地塞米松预处理引起的肝重增加表明药物在肝中的含量明显增加。在甲氨蝶呤给药前后评估血浆肝酶活性表明，细胞抑制剂增强了皮质类固醇的肝毒性。对肝脏中甲氨蝶呤转运体表达的分析表明，Mrp2、Oatp1a4 和 Oat2 的表达上调，而 Mrp3 的表达下调。这些观察结果与胆汁排泄增加和内源性底物结合胆红素的血浆浓度降低相符。相比之下，单次静脉注射地塞米松不会影响甲氨蝶呤的任何药代动力学参数。总之，这些结果表明，与甲氨蝶呤胆汁消除减少相关的肝细胞损伤，以及其升高的肝含量可能导致与地塞米松联合给药时药物的肝毒性增加。此外，还证明了地塞米松对肝和肾中阴离子药物转运蛋白的蛋白表达有影响。
