As in the case of other heavy metals, a considerable body of evidence suggests that overexposure to uranium may cause pathological alterations to the kidneys in both humans and animals. In the present work, our aim was to analyze the available data from a critical perspective that should provide a view of the real danger of the nephrotoxicity of this metal for human beings. A further aim was to elaborate a comparative compilation of the renal pathophysiological data obtained in humans and experimental animals with a view to gaining more insight into our knowledge of the mechanisms of action and renal damage. Finally, we address the existing perspectives for the improvement of diagnostic methods and the treatment of intoxications by uranium, performing an integrated analysis of all these aspects.

P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell’s apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug–drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including in silico, in vitro, ex vivo, and in vivo methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.

The antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.

Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

Amiodarone is an antiarrhythmic drug now more frequently used after a number of years in which the use had been on the decline due to a number of studies which reported side effects such as chronic toxicity, primarily in the lungs, liver and thyroid glands. Additionally, in some patients an increase in serum creatinine was noted, however the effect of amiodarone on renal function had never been closely examined. Thus, the aim of our study was to analyse the effects of amiodarone on renal function in rats. Experiments were carried out in male Wistar rats divided in two experimental groups: 1) a control group, (n=8), 2) a group that received a daily intraperitoneal injection of amiodarone (50 mg/kg body weight) for 6 days (n=5). At the end of the treatment, renal function was measured by clearance creatinine and acute clearance studies. Renal toxicity was evaluated by urinary N‐acetyl‐glucosamine and alkaline phosphatase. At the end of the experiment, histology studies were done. Rats treated with amiodarone had a higher serum creatinine (182%) and a lower glomerular filtration rate (53%), renal plasma flow (68%) and filtration fraction (62%) than controls. Rats treated with amiodarone also showed an increase in urinary N‐acetyl‐glucosamine (221%) and alkaline phosphatase (4.151%) excretion which corresponds with tubular alterations showed on electron microscopy. In conclusion our data confirm that amiodarone induces acute renal damage in the rat.