TY - JOUR
T1 - Drugs commonly applied to kidney patients may compromise renal tubular uremic toxins excretion
AU - Mihaila, Silvia M.
AU - Faria, João
AU - Stefens, Maurice F.J.
AU - Stamatialis, Dimitrios
AU - Verhaar, Marianne C.
AU - Gerritsen, Karin G.F.
AU - Masereeuw, Rosalinde
PY - 2020/6/12
Y1 - 2020/6/12
N2 - 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.
AB - 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.
KW - Chronic kidney disease management
KW - Drug-toxin interaction
KW - OAT1-mediated transport
KW - Protein-bound uremic toxins
UR - http://www.scopus.com/inward/record.url?scp=85086686371&partnerID=8YFLogxK
U2 - 10.3390/toxins12060391
DO - 10.3390/toxins12060391
M3 - Article
C2 - 32545617
AN - SCOPUS:85086686371
SN - 2072-6651
VL - 12
JO - Toxins
JF - Toxins
IS - 6
M1 - 391
ER -
