期刊
JOURNAL OF PHARMACEUTICAL SCIENCES
卷 106, 期 9, 页码 2551-2557出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2017.04.076
关键词
organic cation transporters; renal clearance; regulatory science; disease states; OCT
资金
- U.S. Food and Drug Administration (FDA) through Medical Countermeasures initiative [U01FD004979]
- U.S. Department of Energy
- FDA
Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [C-14]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-beta-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD. (C) 2017 Published by Elsevier Inc. on behalf of the American Pharmacists Association.
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