leflunomideincreasedtherenalexposureofacyclovirbyinhibitingoat13andmrp2

doi:10.1038/s41401-019-0283-z

	leflunomideincreasedtherenalexposureofacyclovirbyinhibitingoat13andmrp2
	Liao Xiaoying 1; Deng Qiangqiang 2; Han Li 2; Wu Zhitao 2; Peng Zhaoliang 2; Xie Yuan 1; Wang Guangji 1; Aa Jiye 1; Pan Guoyu 2
刊名	actapharmacologicasinica
	2020
卷号	41 期号:1 页码:129
关键词	leflunomide teriflunomide acyclovir organic anion transporter multidrug resistance associated protein (MRP) 2 drugdrug interaction pharmacokinetics
ISSN号	1671-4083
DOI	10.1038/s41401-019-0283-z
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 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC_(50) value of 4.91 μmol/L. TER (5 μmol/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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280742]
专题	中国科学院上海药物研究所
作者单位	1.中国药科大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Liao Xiaoying,Deng Qiangqiang,Han Li,et al. leflunomideincreasedtherenalexposureofacyclovirbyinhibitingoat13andmrp2[J]. actapharmacologicasinica,2020,41(1):129.
APA	Liao Xiaoying.,Deng Qiangqiang.,Han Li.,Wu Zhitao.,Peng Zhaoliang.,...&Pan Guoyu.(2020).leflunomideincreasedtherenalexposureofacyclovirbyinhibitingoat13andmrp2.actapharmacologicasinica,41(1),129.
MLA	Liao Xiaoying,et al."leflunomideincreasedtherenalexposureofacyclovirbyinhibitingoat13andmrp2".actapharmacologicasinica 41.1(2020):129.