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The Effect of Uremic Solutes on the Organic Cation Transporter 2
Kit Wun Kathy Cheung1, Chia-Hsiang Hsueh1, Ping Zhao2
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158; Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.
Abstract:
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 [14C]-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-β-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.
Insights
Uremic solutes in chronic kidney disease (CKD) can inhibit the organic cation transporter 2 (OCT2), affecting drug secretion. However, CKD progression did not show selective effects on OCT2 substrate drug secretion.
Area of Science:
- Pharmacology
- Nephrology
- Drug Metabolism
Background:
- Chronic kidney disease (CKD) involves uremic solute accumulation, impacting drug disposition.
- The organic cation transporter 2 (OCT2) is crucial for renal drug secretion.
- Limited understanding exists on how uremic solutes affect OCT2 function and drug renal clearance in CKD.
Purpose of the Study:
- To investigate the inhibitory effects of uremic solutes on the organic cation transporter 2 (OCT2).
- To assess the impact of CKD progression on the renal secretion of OCT2 substrate drugs.
- To review existing literature for evidence of CKD's effect on basic drug renal secretion.
Main Methods:
- Screening of 72 uremic solutes for inhibition of [14C]-metformin uptake by OCT2.
- Identification of clinically relevant OCT2 inhibitors among screened solutes.
- Analysis of secretory clearance and glomerular filtration rate for 6 OCT2 substrate drugs in CKD stages 2-4.
Main Results:
- Seven uremic solutes inhibited OCT2; three were clinically relevant.
- Dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide were identified as novel OCT2 inhibitors.
- Secretory clearance and GFR decreased in parallel with CKD progression, indicating no selective solute effect on net tubular secretion.
Conclusions:
- CKD-associated uremic solutes can inhibit OCT2, a key transporter for basic drug secretion.
- CKD progression does not appear to selectively impair the tubular secretion of OCT2 substrate drugs.
- Further research with diverse OCT2 substrates is needed to fully understand CKD's differential impact on drug secretion, especially in advanced stages.
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