Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease

Machado, Tacy Santana; Cérini, Claire; Burtey, Stéphane

doi:10.3390/toxins11040209

Cited by 13 publications

(6 citation statements)

References 166 publications

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“…As demonstrated by others, the binding capacity of albumin is diminished in CKD patients, most likely due to posttranslational modifications of albumin sites which could contribute to less efficient transport of uremic toxins by the renal tubular excretory machinery [ 70 , 71 , 72 ], thus resulting in further elevated plasma levels and their well-known consequences. Moreover, studies have revealed that interactions between drugs and uremic toxins could result in altered protein binding affinities [ 73 , 74 , 75 , 76 ].…”

Section: Discussionmentioning

confidence: 99%

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion

Mihăilă

Faria

Stefens

et al. 2020

Toxins

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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) equipped with OAT1 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 for ARBs. This was 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.

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Section: Discussionmentioning

confidence: 99%

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion

Mihăilă

Faria

Stefens

et al. 2020

Toxins

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“…It is described, however, that renal failure leads to the accumulation of uremic toxins in blood and tissues. These toxins can compete with other substrates for plasma protein binding to, for example, albumin [45]. As a result, the free fraction of a substrate of albumin will be increased.…”

Section: Discussionmentioning

confidence: 99%

Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing

et al. 2019

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Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better insight into the degree of hepcidin protein binding is essential to fully understand the biological behavior of hepcidin and interpretation of its measurement in patients. Here, we used peritoneal dialysis to assess human hepcidin protein binding in a functional human setting for the first time. We measured freely circulating solutes in blood and peritoneal fluid of 14 patients with end-stage renal disease undergoing a peritoneal equilibration test to establish a curve describing the relation between molecular weight and peritoneal clearance. Calculated binding percentages of total cortisol and testosterone confirmed our model. The protein-bound fraction of hepcidin was calculated to be 40% (±23%). We, therefore, conclude that a substantial proportion of hepcidin is freely circulating. Although a large inter-individual variation in hepcidin clearance, besides patient-specific peritoneal transport characteristics, may have affected the accuracy of the determined binding percentage, we describe an important step towards unraveling human hepcidin plasma protein binding in vivo including the caveats that need further research.

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“…Although CKD is frequently observed in patients with cancer, many oncologic strategies interfere with kidney function. 61,102,103 CKD induces some changes in drug pharmacokinetics, 104,105 as drug absorption may increase or decrease, although it is poorly quantified. Animal and human studies indicate that drug absorption may increase because of impairment of the gut wall barrier function.…”

Section: Kidney Adverse Effects In the Tki Eramentioning

confidence: 99%

Pharmacology of Tyrosine Kinase Inhibitors

Hulin,

Gelé,

Fenioux

et al. 2023

CJASN

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Tyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with non-kidney clearance being predominant. Due to their limited therapeutic window, many TKI display considerable intra- and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD), among cancer patients is explored in terms of their impact on TKI pharmacokinetics. Lastly, the potential nephrotoxicity associated with TKI is also examined.

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Emerging Roles of Aryl Hydrocarbon Receptors in the Altered Clearance of Drugs during Chronic Kidney Disease

Cited by 13 publications

References 166 publications

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion

Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion

Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing

Pharmacology of Tyrosine Kinase Inhibitors

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