Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2 | |
Liao, Xiao-ying2; Deng, Qiang-qiang3; Han, Li1,3; Wu, Zhi-tao3; Peng, Zhao-liang3; Xie, Yuan2; Wang, Guang-ji2; Aa, Ji-ye2; Pan, Guo-yu1,3 | |
刊名 | ACTA PHARMACOLOGICA SINICA |
2020 | |
卷号 | 41期号:1页码:129-137 |
关键词 | leflunomide teriflunomide acyclovir organic anion transporter multidrug resistance associated protein (MRP) 2 drug-drug interaction pharmacokinetics |
ISSN号 | 1671-4083 |
DOI | 10.1038/s41401-019-0283-z |
通讯作者 | Aa, Ji-ye(jiyea@cpu.edu.cn) ; Pan, Guo-yu(gypan@simm.ac.cn) |
英文摘要 | Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 mu mol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 mu mol/L. TER (5 mu mol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration. |
资助项目 | Organ Reconstruction and Manufacturing Strategic Priority Research Program of the Chinese Academy of Sciences[XDA16020205] ; National Natural Science Foundation of China[81872927] ; National Key Special Project of Science and Technology for Innovation Drugs of China[2015zx09501001] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences[CASIMM0120184005] |
WOS关键词 | NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; ORGANIC ANION TRANSPORTERS ; INTRAVENOUS ACYCLOVIR ; RHEUMATOID-ARTHRITIS ; ANTIVIRAL RESISTANCE ; METABOLITE A771726 ; PHARMACOKINETICS ; METHOTREXATE ; ZOSTER ; RISK |
WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
语种 | 英语 |
出版者 | NATURE PUBLISHING GROUP |
WOS记录号 | WOS:000505540800014 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/282359] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Aa, Ji-ye; Pan, Guo-yu |
作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Liao, Xiao-ying,Deng, Qiang-qiang,Han, Li,et al. Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2[J]. ACTA PHARMACOLOGICA SINICA,2020,41(1):129-137. |
APA | Liao, Xiao-ying.,Deng, Qiang-qiang.,Han, Li.,Wu, Zhi-tao.,Peng, Zhao-liang.,...&Pan, Guo-yu.(2020).Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.ACTA PHARMACOLOGICA SINICA,41(1),129-137. |
MLA | Liao, Xiao-ying,et al."Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2".ACTA PHARMACOLOGICA SINICA 41.1(2020):129-137. |
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