JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats

Wen, Shijie; Wang, Changyuan; Huo, Xiaokui; Meng, Qiang; Liu, Zhihao; Yang, Shilei; Zhu, Yanna; Sun, Huijun; Ma, Xiaodong; Liu, Kexin

doi:10.1016/j.toxlet.2018.06.1220

Cited by 35 publications

(23 citation statements)

References 28 publications

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“…Vancomycin is not significantly metabolised in humans. Its elimination primarily depends on renal function [29,32] (with non-renal clearance being probably < 5% of the total drug clearance), which the current model and proposed dosing strategies fully consider, and its plasma levels are not influenced by the activity of renal transport systems [33] . Moreover, all current data were adjusted to a standard creatinine clearance of 100 mL/min for a nominal 70-kg subject, allowing easy comparison and translation to patients with different renal function and weight.…”

Section: Discussionmentioning

confidence: 99%

Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

Nguyen

Delattre

et al. 2019

International Journal of Antimicrobial Agents

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Objectives: Despite extensive clinical use, limited data are available on optimal loading and maintenance doses of vancomycin in critically ill patients. This study aimed to develop a rational approach for optimised dosage of vancomycin given in a continuous infusion in critically ill patients. Methods: Vancomycin pharmacokinetic (PK) data (total serum concentrations) were obtained from 55 intensive care unit (ICU) patients (Bach Mai Hospital, Hanoi, Vietnam) receiving a 20 mg/kg loading dose followed by continuous infusion stratified by creatinine clearance (CLCr). Population PK modelling and Monte Carlo simulations were performed using a nonlinear mixed-effects modelling (NONMEM) program for a target of 20-30 mg/L to optimise efficacy and minimise nephrotoxicity. Results: A two-compartment model with first-order elimination best fitted the PK data with central and peripheral volumes of distribution of 1.01 and 2.39 L/kg, respectively (allometric scaling to a 70 kg standard subject). The population total clearance of 3.63 L/h was only explained by renal function in the covariate and final model. The simulations showed that a 25-mg/kg loading dose infused over 90 minutes was optimal to reach the target range. The optimal maintenance dose for low renal function (CLCr < 45 mL/min) was 10 0 0-150 0 mg/day. For augmented renal clearance (CLCr > 130 mL/min) the dose should be up to 3500 mg/day or even 4500 mg/day to achieve adequate exposure. These simulated maintenance doses were larger than previously proposed for non-ICU patients. Conclusion: Large loading and maintenance doses of vancomycin are generally needed in critically ill patients. Because of high interindividual variability in vancomycin PK, drug monitoring may still be necessary.

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Section: Discussionmentioning

confidence: 99%

Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

Nguyen

Delattre

et al. 2019

International Journal of Antimicrobial Agents

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“…This decrease in transporter expression with vancomycin could lead to accumulation of endogenous endotoxins thus contributing to VIKI. Compound JBP485, a dipeptide isolated from the human placenta, demonstrated antioxidant and antiapoptotic effects and regulated the expression of the proximal tubule transporters to enhance renal excretion of endogenous uremic toxins and attenuate VIKI in rats without affecting plasma concentrations of vancomycin 125 …”

Section: Potential Strategies For Preventionmentioning

confidence: 99%

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

et al. 2020

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Vancomycin is a recommended therapy in multiple national guidelines. Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin-mediated kidney injury. In this review, historic and contemporary rates of vancomycin-induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge that may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.

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“…The experimental protocol was performed according to our previous description (Wen et al, 2018). In brief, total RNA isolation and cDNA synthesis was carried out by using an RNAiso Plus® Reagent kit and SYBR® Premix Ex Taq™ kit, respectively (Takara Biotechnology, Dalian, China).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

Catalpol alleviates adriamycin‐induced nephropathy by activating the SIRT1 signalling pathway in vivo and in vitro

Zhang

Meng

et al. 2019

British J Pharmacology

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Background and Purpose: Catalpol, a water-soluble active ingredient isolated from Rehmannia glutinosa, exhibits multiple pharmacological activities. However, the mechanism(s) underlying protection against renal injury by catalpol remains unknown. Experimental Approach: Adriamycin-induced kidney injury models associated with podocyte damage were employed to investigate the nephroprotective effects of catalpol. In vivo, TUNEL and haematoxylin-eosin staining was used to evaluate the effect of catalpol on kidney injury in mice. In vitro, effects of catalpol on podocyte damage induced by adriamycin was determined by ELISA kit, flow cytometry, Hoechst 33342, and TUNEL staining. The mechanism was investigated by siRNA, EX527, and docking simulations. Key Results: In vivo, catalpol treatment significantly improved adriamycin-induced kidney pathological changes and decreased the number of apoptotic cells. In vitro, catalpol markedly decreased the intracellular accumulation of adriamycin and reduced the calcium ion level in podocytes and then attenuated apoptosis. Importantly, the regulatory effects of catalpol on sirtuin 1 (SIRT1), multidrug resistance-associated protein 2 (MRP2), and the TRPC6 channel were mostly abolished after incubation with SIRT1 siRNA or the SIRT1-specific inhibitor EX527. Furthermore, docking simulations showed that catalpol efficiently oriented itself in the active site of SIRT1, indicating a higher total binding affinity score than that of other SIRT1 activators, such as resveratrol, SRT2104, and quercetin. Conclusion and Implications: Taken together, our results suggest that catalpol exhibits strong protective effects against adriamycin-induced nephropathy by inducing SIRT1-mediated inhibition of TRPC6 expression and enhancing MRP2 expression. 1 | INTRODUCTION The anthracycline antibiotic adriamycin, a broad-spectrum anti-tumour drug, has been widely used to treat various cancers (Rivankar, 2014). The toxic side effect of adriamycin, mainly associated with cardiotoxicity (Octavia et al., 2012), limits its clinical applications. It has been noted that nephrotoxicity can be induced by adriamycin in rodents but rarely occurs in humans. Anthracycline-induced chronic kidney damage was reported early in 1970 (Sternberg, 1970) and since then animal models of adriamycin-induced kidney injury have been widely established (Bucciarelli, Binazzi, Santori, & Vespasiani, 1976; Chen et al., 2015). It has been reported that the adriamycin-induced classic nephrotoxicity model is very similar to human progressive chronic renal disease (Ajith, Aswathy, & Hema, 2008). Subsequently, Jiangnan Zhang and Ran Bi should be considered joint first author.

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JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats

Cited by 35 publications

References 28 publications

Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

Determination of optimal loading and maintenance doses for continuous infusion of vancomycin in critically ill patients: Population pharmacokinetic modelling and simulations for improved dosing schemes

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

Catalpol alleviates adriamycin‐induced nephropathy by activating the SIRT1 signalling pathway in vivo and in vitro

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