Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach

Rivera-Velez, Sol M.; Broughton-Neiswanger, Liam E.; Suarez, Martin A.; Slovak, Jennifer E.; Hwang, Julianne K.; Navas, Jinna; Leung, Amy Wing-Sze; Piñeyro, Pablo; Villarino, Nicolás F.

doi:10.1111/jvp.12788

Cited by 5 publications

(12 citation statements)

References 36 publications

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“…Within the kidney, the proximal convoluted tubule is the primary site of acid secretion, suggesting this may be a site injured following meloxicam administration. Histopathology studies of kidney samples collected from a subset of cats used in this study confirmed that repeated administration of meloxicam damages proximal renal tubules (Rivera‐Velez et al., 2019). Additionally, a recent related study investigating metabolite alterations within renal cortical and medullary samples of cats treated with meloxicam found that, in general, organic acids are decreased in medullas from meloxicam‐treated cats (Rivera‐Velez et al., 2019).…”

Section: Discussionsupporting

confidence: 77%

“…Histopathology studies of kidney samples collected from a subset of cats used in this study confirmed that repeated administration of meloxicam damages proximal renal tubules (Rivera‐Velez et al., 2019). Additionally, a recent related study investigating metabolite alterations within renal cortical and medullary samples of cats treated with meloxicam found that, in general, organic acids are decreased in medullas from meloxicam‐treated cats (Rivera‐Velez et al., 2019). Taken together, these data permit us to speculate that meloxicam may impair renal organic acid excretion, leading to retention of organic acids within the plasma.…”

Section: Discussionsupporting

confidence: 77%

“…All cats in the meloxicam treatment group for both the training and testing sets had clinical pathologic and renal histologic evidence of kidney injury (Rivera‐Velez et al., 2019) with the exception of one cat (M15) in the training set.…”

Section: Methodsmentioning

confidence: 99%

“…A recent study from our laboratory published by Rivera et al discovered that the repeated administration of meloxicam to cats altered at least 40 metabolic pathways in the renal cortex and medulla (Rivera‐Velez et al., 2019). Another study from the same group reported that meloxicam altered the plasma and urine lipidome of cats (Rivera‐Velez et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacometabolomics with a combination of PLS‐DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Broughton-Neiswanger

Rivera-Velez

Suarez

et al. 2020

Vet Pharm & Therapeutics

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Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine‐learning algorithms, partial least squares discriminant analysis (PLS‐DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam‐ and saline‐treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam‐treated from saline‐treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID‐induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacometabolomics with a combination of PLS‐DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Broughton-Neiswanger

Rivera-Velez

Suarez

et al. 2020

Vet Pharm & Therapeutics

Self Cite

View full text Add to dashboard Cite

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“…Lipidomics, which is a subset of metabolomics, mainly contributes in the evaluation of various lipid species in complex biological samples 18 . Combined metabolomics and lipidomics approaches have been widely applied and used to assess the pathophysiological pathways related to disease progression, identify biomarkers and monitor the underlying mechanism of drug effects and toxicity 19 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics

Rashid

Lee

Jung

2020

Sci Rep

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PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various cancer types. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. After 3 weeks of PP242 treatment, a reduction in tumor size and weight was observed without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, in this study, it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. This study reveals new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further to facilitate the understanding of PP242 effects in the clinical application.

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Comparative metabolomics and lipidomics study to evaluate the metabolic differences between first‐ and second‐generation mammalian or mechanistic target of rapamycin inhibitors

Rashid

Lee

Park

et al. 2021

Biomedical Chromatography

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Mammalian or mechanistic target of rapamycin (mTOR) drives its fundamental cellular functions through two distinct catalytic subunits, mTORC1 and mTORC2, and is frequently dysregulated in most cancers. To treat cancers, developed mTOR inhibitors have been classified into first and second generations based on their ability to inhibit single (first‐generation) and dual (second‐generation) mTOR subunits. However, the underlying metabolic differences due to the effects of first‐ and second‐generation mTOR inhibitors have not been clearly evaluated. In this study, rapamycin (sirolimus) and AZD8055 and PP242 were selected as first‐ and second‐generation mTOR inhibitors, respectively, to evaluate the metabolic differences due to these two generations of mTOR inhibitors after a single oral dose using untargeted metabolomics and lipidomics approaches. The metabolic differences at each time point were compared using multivariate analysis. The multivariate and data analyses showed that metabolic disparity was more prominent within 8 h after drug administration and a broad class of metabolites were affected by the administration of both generations of mTOR inhibitors. Among the metabolite classes, changes in the pattern of fatty acids and glycerophospholipids were opposite, specifically at 4 and 8 h between the two generations of mTOR inhibitors. We speculate that the inhibition of the mTORC2 subunit by the second‐generation mTOR inhibitor may have resulted in a distinct metabolic pattern between the first‐ and second‐generation inhibitors. Finally, the findings of this study could assist in a more detailed understanding of the key metabolic differences caused by first‐ and second‐generation mTOR inhibitors.

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Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach

Cited by 5 publications

References 36 publications

Pharmacometabolomics with a combination of PLS‐DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Pharmacometabolomics with a combination of PLS‐DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics

Comparative metabolomics and lipidomics study to evaluate the metabolic differences between first‐ and second‐generation mammalian or mechanistic target of rapamycin inhibitors

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