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Kidney Week

Abstract: TH-PO371

Drugs Applied to Kidney Patients May Interact with Uremic Toxins for Renal Excretion

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Masereeuw, Rosalinde, Utrecht Institute for Pharmaceutical Sciences, Utrecht,, Utrecht, Netherlands
  • Mihaila, Silvia M., University Medical Center Utrecht, Utrecht, Netherlands
  • Verhaar, Marianne C., University Medical Center Utrecht, Utrecht, Netherlands
  • Stamatialis, Dimitrios, University of Twente - Faculty of Science and Technology, Enschede, Netherlands
  • Gerritsen, Karin G., University Medical Center Utrecht, Utrecht, Netherlands
Background

Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUT). In CKD, excretion of PBUTs is compromised leading to their accumulation, exacerbating CKD and contributing to uremic complications. Recently, we showed that conditionally immortalized proximal tubule epithelial cells (ciPTECs) expressing OAT and cultured on biofunctionalized membranes, actively secrete PBUTs [1,2]. However, OAT1 also handles a wide range of drugs. Here, we investigated the interaction between drugs commonly prescribed to CKD patients and PBUTs for OAT1-mediated transport, using indoxyl sulfate (IS) as prototype PBUT.

Methods

A panel of 9 drugs was screened for interactions in ciPTECs-OAT1 monolayers in the presence (+) and absence (-) of IS, at a uremic concentration (110 µM). To evaluate OAT1 function, fluorescein was used as substrate and its uptake was measured using a multi-plate reader.

Results

Our results show that ACE-inhibitors and cimetidine have either no or a slight effect at non-therapeutical concentrations on OAT1-mediated fluorescein uptake. On the contrary, ATII-inhibitors, statins and furosemide significantly reduced fluorescein uptake, with the highest potency for ATII-inhibitors. This trend was maintained in presence of IS, suggesting that these drugs could negatively influence secretion of PBUTs by ciPTECs (Table 1).

Conclusion

Drugs commonly used by kidney patients may compromise endogenous waste product clearance. Further studies should address the transepithelial excretion of PBUTs in the presence of drugs. A similar evaluation in CKD patients would validate our findings.

1. Jansen J, et al, Sci. Rep. 6:26715, 2016; 2. Nieskens TTG, et al, AAPS J. 18: 2, 2016

Table 1. OAT1-mediated fluorescein uptake: IC50 (µM) in the absence (-) and presence (+) of IS *
DrugIC50 - ISIC50 + ISDrugIC50 - ISIC50 + IS
 ACE inhibitors  Statins 
CaptoprilNTNTSimvastatin21.3 ± 3.871.8 ± 27.3
EnalaprilateNTNTPravastatin23.2 ± 8.340.9 ± 9.2
LisinoprolNo effectNo effect Others 
 ATII inhibitors Furosemide28.1 ± 9.144.7 ± 12.4
Losartan8.6 ± 2.513.9 ± 4.9CimetidineNTNo effect
Valsartan11.5 ± 3.516.1 ± 3.6   

* Values are given as mean of two independent observations. NT=non-therapeutical concentration.

Funding

  • Government Support - Non-U.S.