Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor alpha Activation
文献类型：期刊论文
| 作者 | Wang, Le; Ma, Leilei; Lin, Yunfei; Liu, Xing; Xiao, Ling; Zhang, Yiting; Xu, Ye; Zhou, Hu ; Pan, Guoyu
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| 刊名 | MOLECULAR PHARMACOLOGY
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| 出版日期 | 2018-06-01 |
| 卷号 | 93期号:6页码:563-574 |
| ISSN号 | 0026-895X |
| DOI | 10.1124/mol.117.110593 |
| 文献子类 | Article |
| 英文摘要 | Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7-hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor alpha (PPAR alpha), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPAR alpha-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPAR alpha agonists and Mrp substrates in the clinic. |
| WOS关键词 | ARYL-HYDROCARBON RECEPTOR ; 7-HYDROXYMETHOTREXATE IN-VIVO ; PPAR-ALPHA ; RHEUMATOID-ARTHRITIS ; SPECIES-DIFFERENCES ; LIVER FIBROSIS ; ACID SYNTHESIS ; ABCG2 BCRP1 ; ABCC2 MRP2 ; INDUCTION |
| 资助项目 | "Organ Reconstruction and Manufacturing" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA16000000] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences[CASIMM0120163012] ; Hundred Talents Program of the Chinese Academy of Sciences[00000000] ; National Science Foundation of China[81573499] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000435117100001 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279723]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Pan, Guoyu |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Le,Ma, Leilei,Lin, Yunfei,et al. Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor alpha Activation[J]. MOLECULAR PHARMACOLOGY,2018,93(6):563-574. |
| APA | Wang, Le.,Ma, Leilei.,Lin, Yunfei.,Liu, Xing.,Xiao, Ling.,...&Pan, Guoyu.(2018).Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor alpha Activation.MOLECULAR PHARMACOLOGY,93(6),563-574. |
| MLA | Wang, Le,et al."Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor alpha Activation".MOLECULAR PHARMACOLOGY 93.6(2018):563-574. |
入库方式： OAI收割
来源：上海药物研究所
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