Abstract
In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake.We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equippedwithOAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay.We show that selected ARBs and furosemide significantly reduced fluorescein uptake,with the highest potency forARBs. Thiswas exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.
Original language | English |
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Article number | 391 |
Number of pages | 16 |
Journal | Toxins |
Volume | 12 |
Issue number | 6 |
DOIs | |
Publication status | Published - 1 Jun 2020 |
Funding
Funding: This research was funded by the Strategic Agency of the University of Twente, University of Utrecht and University Medical Center Utrecht and the “European Uremic Toxin working group” (EUTox) of the “European Society for Artificial Organs” (ESAO) endorsed by the “European Renal Association-European Dialysis Transplantation Association” (ERA-EDTA), of which D. Stamatialis and R. Masereeuw are members. M.C. Verhaar and R. Masereeuw kindly acknowledge support by RegMed XB (REGenerative MEDicine crossing Borders) powered by Top Sector Life Sciences & Health (Health~Holland).
Keywords
- Chronic kidney disease management
- Drug-toxin interaction
- OAT1-mediated transport
- Protein-bound uremic toxins