Severe renal toxicity due to intermediate-dose methotrexate

Stark, A N; Jackson, Graham; Carey, Peter; Arfeen, S.; Proctor, Stephen J.

doi:10.1007/bf00257626

Cited by 34 publications

(20 citation statements)

References 8 publications

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“…Although it has been reported that MTX also has negative effects on the excretion of CEX into the urine by glomerular filtration and tubular secretion, 22,23 there were no significant differences in the terminal elimination rate constant (Ke) among the different groups in the present study (data not shown) because NaHCO3 was used to minimize the adverse effects of MTX on kidney function. Cephalexin is a hydrophilic ionic compound that is largely absorbed from the small intestine via the active transporter PEPT1 and it is metabolized very little.…”

Section: Discussioncontrasting

confidence: 56%

“…Cephalexin is a hydrophilic ionic compound that is largely absorbed from the small intestine via the active transporter PEPT1 and it is metabolized very little. Although it has been reported that MTX also has negative effects on the excretion of CEX into the urine by glomerular filtration and tubular secretion, 22,23 there were no significant differences in the terminal elimination rate constant (Ke) among the different groups in the present study (data not shown) because NaHCO3 was used to minimize the adverse effects of MTX on kidney function. Changes in the Cmax and AUCCEX observed in MTX-treated rats could be explained as the result of functional changes in the intestinal absorption of CEX by carrier-mediated transport systems and/or passive diffusion through the tight junction.…”

Section: Discussioncontrasting

confidence: 56%

See 1 more Smart Citation

Changes In Absorptive Function Of Rat Intestine Injured By Methotrexate

Naruhashi

Nadai

Nakao

et al. 2000

Clin Exp Pharma Physio

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1. Methotrexate (MTX), an anticancer drug, has been shown to induce acute injury in the small intestine. The present study was designed to investigate the in vivo absorptive function of the small intestine injured by MTX using an amino-beta-lactam antibiotic cephalexin (CEX). Time-dependent changes in diamine oxidase (DAO) and alkaline phosphatase (ALP) activity in the small intestine and histopathological findings were also measured in rats treated with MTX (20 mg/kg). 2. Most severe mucosal damage was observed 2 days after MTX treatment and the area under the plasma concentration-time curve of CEX (AUC(CEX)) following oral administration of 20 mg/kg tended to decrease. Thereafter, the AUC(CEX) increased significantly and the histopathological changes diminished within 5 days. 3. Both villus height and mucosal weight followed the same pattern, decreasing in the first 2 or 3 days following treatment, increasing on the 5th day and returning to control levels by the 10th day. Methotrexate-induced changes in the mucosal wet weight/whole intestinal weight ratio were significantly correlated with those of AUC(CEX), but did not correlate with mucosal DAO and ALP activity. 4. These findings provide evidence that the change in the total amount of CEX is an index of the active transport function, probably by intestinal peptide transporter (PEPT1), and is well reflected by histopathological changes in the intestinal mucosa induced by MTX. In addition, there is a possibility that this method could be applied in the clinical setting for diagnosis of intestinal status and absorptive function.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussioncontrasting

confidence: 56%

Changes In Absorptive Function Of Rat Intestine Injured By Methotrexate

Naruhashi

Nadai

Nakao

et al. 2000

Clin Exp Pharma Physio

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“…In contrast, if too little LV is given it can lead to the MTX associated toxicities. Although LV administration is based on the individual’s clearance of MTX, there are still reports of toxicity and death in patients receiving HDMTX 19-21. These studies imply that earlier commencement and an increase in the amount of LV given could have prevented these toxicities and fatalities.…”

Section: Discussionmentioning

confidence: 99%

Evaluating Performance of a Decision Support System to Improve Methotrexate Pharmacotherapy in Children and Young Adults With Cancer

Dombrowsky

Jayaraman

Narayan

et al. 2011

Therapeutic Drug Monitoring

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The management of high-dose methotrexate (MTX) therapy in patients with cancer depends on the routine monitoring of drug exposures in conjunction with leucovorin (LV), urine pH, patient hydration and other clinical indices of patient well-being. A key factor in patient oversight is the facilitation of MTX clearance in order to minimize drug-related toxicity. The aim of this investigation was to evaluate the performance of a clinical decision support system and Bayesian forecasting algorithm in the prediction of MTX concentrations and assessment of LV dosing requirements in pediatric and young adult cancer patients based on the current practice at the Children’s Hospital of Philadelphia. Fifty patients ranging in age from 8 months to 21 years (weight range,7.6 to 163.3 kg) contributing 80 total dosing events (183 MTX serum concentrations) were studied. The forecasting model was able to consistently predict future MTX concentrations with the knowledge of one prior concentration and continued to improve with additional concentration data made available through daily therapeutic drug monitoring. Precision was good at 12.9% with low bias at 2.2%. Comparison between the decision support system recommendations for LV rescue relative to the actual LV administration was also made. Sixteen patients would have initiated rescue therapy earlier, 7 patients would have received a larger dose (42 smaller) and LV would have been given less often for 37 patients. The forecasting algorithm in the MTX dashboard was reasonably accurate in predicting MTX concentrations and should improve further as the underlying model and prediction algorithm evolves. This decision support system can be useful in helping physicians decide if a patient is clearing MTX as expected or if more aggressive rescue therapy is warranted.

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“…Resulting sustained and elevated plasma concentration causes a marked enhancement of MTX's other toxicities. 5 Thus, finding a nephroprotective agent is mandatory for the safe use of this important drug. Heat-shock proteins (HSPs) are highly conserved and ubiquitously expressed molecular chaperones that help restore normal cellular function following an injury.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of propolis on methotrexate-induced kidney injury in the rat

2016

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Objectives Propolis is a potent antioxidant and a free radical scavenger. Pharmacological induction of heat shock proteins (HSPs) has been investigated for restoring normal cellular function following an injury. In this study, effect of propolis on HSP-70 expression in methotrexate-induced nephrotoxicity and direct preventive effect of propolis in this toxicity were investigated. Material and methods A total of 40 male Wistar albino rats were divided into four groups: Group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20 mg/kg. Groups 3 and 4 received 100 mg/kg/day propolis (by oral gavage) for 15 d by the first day of the experimental protocol. Then the rats were decapitated under ketamine esthesia and their kidney tissues were removed. HSP-70 expression, apoptosis, and histopathological damage scores were then compared. Results MTX caused epithelial desquamation into the lumen of the tubules, dilatation, and congestion of the peritubular vessels and renal corpuscles with obscure Bowman's space. The number of apoptotic cells (p ¼ 0.000) and HSP-70 (p ¼ 0.002) expression were increased in group 2. Propolis prevented the rise in number of apoptotic cells (p ¼ 0.017), HSP-70 (p ¼ 0.000) expression, and improved kidney morphology. Conclusions It was found that methotrexate gives rise to serious damage in the kidney and propolis is a potent antioxidant agent in preventing kidney injury. ARTICLE HISTORY

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Severe renal toxicity due to intermediate-dose methotrexate

Cited by 34 publications

References 8 publications

Changes In Absorptive Function Of Rat Intestine Injured By Methotrexate

Changes In Absorptive Function Of Rat Intestine Injured By Methotrexate

Evaluating Performance of a Decision Support System to Improve Methotrexate Pharmacotherapy in Children and Young Adults With Cancer

Protective effect of propolis on methotrexate-induced kidney injury in the rat

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