Toxicokinetics in Renal Disease

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 3741

Special Issue Editor


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Guest Editor
Faculty of Pharmacy and Pharmaceutical Sciences, The University of Alberta, Edmonton, AB, Canada
Interests: pharmacokinetics; toxicology; uremic toxins; pharmacogenomics; drug metabolism; population pharmacokinetic modeling

Special Issue Information

Dear Colleagues,

The kidney plays a critical role in the elimination of xenobiotics. Patients with uncontrolled kidney disease are prone to the development of multiorgan (e.g., hepatic, renal, and cardiac) toxicities. Emerging evidence supports the accumulation of uremic retention solutes in patients with compromised renal function as a potential mechanism for the progression to multiorgan injury. However, relatively little is known about how these uremic toxins are metabolized (i.e., bioactivation vs. deactivation), transported, and excreted from the body. Moreover, their potential to modulate metabolism and biological processes, which could lead to clinically significantly pharmacokinetic–pharmacodynamic interactions, remain to be systematically characterized. This Special Issue examines the toxicokinetics in renal disease, focusing on uremic toxins, biological markers, and therapeutic agents. We will welcome in vitro, preclinical, and clinical data obtained using well-established and advanced experimental techniques.

Dr. Tony K. L. Kiang
Guest Editor

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Keywords

  • toxicokinetics
  • renal disease
  • reaction phenotyping
  • kinetic modeling
  • drug/gene interactions
  • systems pharmacology

Published Papers (1 paper)

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Research

23 pages, 2578 KiB  
Article
Effects of p-Cresol on Oxidative Stress, Glutathione Depletion, and Necrosis in HepaRG Cells: Comparisons to Other Uremic Toxins and the Role of p-Cresol Glucuronide Formation
by Sang Zhu, Yan Rong and Tony K. L. Kiang
Pharmaceutics 2021, 13(6), 857; https://doi.org/10.3390/pharmaceutics13060857 - 09 Jun 2021
Cited by 13 | Viewed by 3213
Abstract
The toxicological effects of p-cresol have primarily been attributed to its metabolism products; however, very little human data are available in the key organ (i.e., liver) responsible for the generation of these metabolites. Experiments were conducted in HepaRG cells utilizing the following [...] Read more.
The toxicological effects of p-cresol have primarily been attributed to its metabolism products; however, very little human data are available in the key organ (i.e., liver) responsible for the generation of these metabolites. Experiments were conducted in HepaRG cells utilizing the following markers of cellular toxicity: 2′-7′-dichlorofluorescein (DCF; oxidative stress) formation, total cellular glutathione (GSH) concentration, and lactate dehydrogenase (LDH; cellular necrosis) release. Concentrations of p-cresol, p-cresol sulfate, and p-cresol glucuronide were determined using validated assays. p-Cresol exposure resulted in concentration- and time-dependent changes in DCF (EC50 = 0.64 ± 0.37 mM at 24 h of exposure) formation, GSH (EC50 = 1.00 ± 0.07 mM) concentration, and LDH (EC50 = 0.85 ± 0.14 mM) release at toxicologically relevant conditions. p-Cresol was also relatively more toxic than 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid, and hippuric acid on all markers. Although the exogenous administration of p-cresol sulfate and p-cresol glucuronide generated high intracellular concentrations of these metabolites, both metabolites were less toxic compared to p-cresol at equal-molar conditions. Moreover, p-cresol glucuronide was the predominant metabolite generated in situ from p-cresol exposure. Selective attenuation of glucuronidation (without affecting p-cresol sulfate formation, while increasing p-cresol accumulation) using independent chemical inhibitors (i.e., 0.75 mM l-borneol, 75 µM amentoflavone, or 100 µM diclofenac) consistently resulted in further increases in LDH release associated with p-cresol exposure (by 28.3 ± 5.3%, 30.0 ± 8.2% or 27.3 ± 6.8%, respectively, compared to p-cresol treatment). These novel data indicated that p-cresol was a relatively potent toxicant, and that glucuronidation was unlikely to be associated with the manifestation of its toxic effects in HepaRG cells. Full article
(This article belongs to the Special Issue Toxicokinetics in Renal Disease)
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