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有机阴离子转运体也介导了亚胺培南与西司他丁之间的药物相互作用。

Organic anion transporters also mediate the drug-drug interaction between imipenem and cilastatin.

作者信息

Zhu Yanna, Huo Xiaokui, Wang Changyuan, Meng Qiang, Liu Zhihao, Sun Huijun, Tan Aiping, Ma Xiaodong, Peng Jinyong, Liu Kexin

机构信息

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.

College (Institute) of Integrative Medicine, Dalian Medical University, Dalian 116044, China.

出版信息

Asian J Pharm Sci. 2020 Mar;15(2):252-263. doi: 10.1016/j.ajps.2018.11.006. Epub 2018 Dec 28.

DOI:10.1016/j.ajps.2018.11.006
PMID:32373203
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7193450/
Abstract

This study aimed to clarify that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between imipenem and cilastatin. After co-administration with imipenem, the plasma concentrations and the plasma concentration-time curve () of cilastatin were significantly increased, while renal clearance and cumulative urinary excretion of cilastatin were decreased. At the same time, imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1 (hOAT1)-HEK293 and human OAT3 (hOAT3)-HEK293 cells. Probenecid, p-aminohippurate, and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1- and hOAT3-HEK 293 cells, respectively. The uptakes of imipenem and cilastatin in hOAT1- and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells. Moreover, the values of cilastatin were increased in the presence of imipenem with unchanged , indicating that imipenem inhibited the uptake of cilastatin in a competitive manner. When imipenem and cilastatin were co-administered, the level of imipenem was higher compared with imipenem alone both and . But, cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1 (DPEP1) was silenced by RNAi technology in hOAT1- and hOAT3-HEK 293 cells. In conclusion, imipenem and cilastatin are the substrates of OAT1 and OAT3. OAT1 and OAT3 mediate the DDI between imipenem and cilastatin. Meanwhile, cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.

摘要

本研究旨在阐明有机阴离子转运体（OATs）介导亚胺培南与西司他丁之间的药物相互作用（DDI）。与亚胺培南合用时，西司他丁的血浆浓度及血浆浓度-时间曲线（）显著升高，而西司他丁的肾清除率和累积尿排泄量降低。同时，亚胺培南显著抑制西司他丁在大鼠肾切片以及人OAT1（hOAT1）-HEK293和人OAT3（hOAT3）-HEK293细胞中的摄取。丙磺舒、对氨基马尿酸和苄青霉素分别抑制西司他丁和亚胺培南在大鼠肾切片以及hOAT1-和hOAT3-HEK 293细胞中的摄取。亚胺培南和西司他丁在hOAT1-和hOAT3-HEK 293细胞中的摄取显著高于在mock-HEK-293细胞中的摄取。此外，在存在亚胺培南时，西司他丁的 值升高，而 值不变，表明亚胺培南以竞争性方式抑制西司他丁的摄取。当亚胺培南与西司他丁合用时，亚胺培南的水平在 和 时均高于单独使用亚胺培南时。但是，当通过RNAi技术使hOAT1-和hOAT3-HEK 293细胞中的脱氢肽酶-1（DPEP1）沉默时，西司他丁显著抑制亚胺培南的摄取。总之，亚胺培南和西司他丁是OAT1和OAT3的底物。OAT1和OAT3介导亚胺培南与西司他丁之间的DDI。同时，西司他丁还通过抑制肾中由OAT1和OAT3介导的亚胺培南摄取，作为一种补充来减少亚胺培南的水解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/f8d77db23a2a/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/bc5ef22f5371/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/9e142a1426ce/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/896fe41d10d9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/6017fa039a0a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/8cc022cabb3f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/61628cf7088d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/2104581bf770/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/19fabd08ef92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/f8d77db23a2a/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/bc5ef22f5371/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/9e142a1426ce/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/896fe41d10d9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/6017fa039a0a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/8cc022cabb3f/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/61628cf7088d/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/2104581bf770/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/19fabd08ef92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f09d/7193450/f8d77db23a2a/gr8.jpg

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