Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Iwamura, Atsushi; Watanabe, Kiichi; Akai, Shigeyasu; Nishinosono, Tsubasa; Tsuneyama, Koichi; Oda, Shingo; Kume, Toshiyuki; Yokoi, Tsuyoshi

doi:10.1124/dmd.116.069575

Cited by 20 publications

(16 citation statements)

References 50 publications

(63 reference statements)

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“…Although withdrawn from the market due to its tendency to cause serious anaphylaxis in an unpredictable subset of the population, zomepirac is still being actively researched and recent publications have focused on kidney toxicity using mice pretreated with esterase and glutathione synthesis inhibitors (Iwamura et al, 2016). In these experiments, zomeripac acyl glucuronide concentrations in the kidney correlated with biomarkers of kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Safety Assessment of Acyl Glucuronides—A Simplified Paradigm

2018

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While simple - (ether-linked) and-glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of the parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging. In this Commentary, we discuss alternative (non-acyl glucuronide) mechanisms by which carboxylic acids may cause serious adverse reactions, and propose a novel, practical approach to compare systemic exposure to acyl glucuronide metabolites in humans to that in animal species used in preclinical safety assessment based on relative estimates of the total body burden of these circulating conjugates.

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Section: Discussionmentioning

confidence: 99%

Safety Assessment of Acyl Glucuronides—A Simplified Paradigm

2018

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“…The levels of lipid peroxidation in muscles were analyzed by evaluating malondialdehyde (MDA) concentrations using a TBARS assay kit (Oxford Biomedical Research) according to previously described methods (Iwamura et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…SOD activity was determined by the inhibition of the formation of the watersoluble formazan, which was evaluated by measuring the absorbance at 450 nm. The levels of lipid peroxidation in muscles were analyzed by evaluating malondialdehyde (MDA) concentrations using a TBARS assay kit (Oxford Biomedical Research) according to previously described methods (Iwamura et al, 2016).…”

Section: Oxidative Stress Analysismentioning

confidence: 99%

Reduced metabolic capacity in fast and slow skeletal muscle via oxidative stress and the energy‐sensing of AMPK/SIRT1 in malnutrition

et al. 2021

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The effects of malnutrition on skeletal muscle result in not only the loss of muscle mass but also fatigue intolerance. It remains unknown whether the metabolic capacity is related to the fiber type composition of skeletal muscle under malnourished condition although malnutrition resulted in preferential atrophy in fast muscle. The purpose of the present study was to investigate the effects of metabolic capacity in fast and slow muscles via the energy‐sensing of AMPK and SIRT1 in malnutrition. Wistar rats were randomly divided into control and malnutrition groups. The rats in the malnutrition group were provided with a low‐protein diet, and daily food intake was limited to 50% for 12 weeks. Malnutrition with hypoalbuminemia decreased the body weight and induced the loss of plantaris muscle mass, but there was little change in the soleus muscle. An increase in the superoxide level in the plasma and a decrease in SOD‐2 protein expression in both muscles were observed in the malnutrition group. In addition, the expression level of AMPK in the malnutrition group increased in both muscles. Conversely, the expression level of SIRT1 decreased in both muscles of the malnutrition group. In addition, malnutrition resulted in a decrease in the expression levels of PGC‐1α and PINK protein, and induced a decrease in the levels of two key mitochondrial enzymes (succinate dehydrogenase and citrate synthase) and COX IV protein expression in both muscles. These results indicate that malnutrition impaired the metabolic capacity in both fast and slow muscles via AMPK‐independent SIRT1 inhibition induced by increased oxidative stress.

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“…Recently, AG-mediated cytotoxic mechanisms involving oxidative stress have been reported. 36,37 In addition, AGs play roles in drug–drug interactions via membrane transporters 17,38,39 as well as through CYP2C8 inhibition. 40−42 Various factors that affect the safety of AGs, including the rates of formation, elimination, and aglucuronidation; their intrinsic reactivity; and the potential proteins being targeted, 43 as well as the molecular mechanisms underlying AG-induced toxicities, 44 all remain to be elucidated fully.…”

Section: Introductionmentioning

confidence: 99%

Chemo-Enzymatic Synthesis, Structural and Stereochemical Characterization, and Intrinsic Degradation Kinetics of Diastereomers of 1-β-O-Acyl Glucuronides Derived from Racemic 2-{4-[(2-Methylprop-2-en-1-yl)amino]phenyl}propanoic Acid

et al. 2018

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Alminoprofen, ( RS )-2-{4-[(2-methylprop-2-en-1-yl)amino]phenyl}propanoic acid (ALP) 1 , is a racemic drug categorized as a 2-arylpropanoic acid-class nonsteroidal anti-inflammatory drug. Pharmacokinetic studies of 1 in patients have revealed that the corresponding acyl glucuronide 5 is a major urinary metabolite, but little is known about the structure and stereochemistry of 5 . The present work describes the synthesis of a diastereomeric mixture of 1-β- O -acyl glucuronides (2 RS )- 5 from 1 and methyl 2,3,4-tri- O -acetyl-1-bromo-1-deoxy-α- d -glucopyranuronate 2 using our chemo-enzymatic method that has complete specificity for the β-configuration. The structure of (2 RS )- 5 was characterized by 1 H and 13 C NMR spectroscopy and high-resolution mass spectrometry as well as by complete hydrolysis by β-glucuronidase. The absolute stereochemistry of (2 RS )- 5 was determined by comparison with (2 R )- 5 synthesized alternatively from (2 R )- 1 and 2 . Compound (2 R )- 1 was prepared in two steps starting from chiral ( R )-2-(4-nitrophenyl)propanoic acid (2 R )- 6 . Chiral resolution of (2 RS )- 1 was achieved using a chiral high-performance liquid chromatography column, and its stereochemistry was determined by comparison with (2 R )- 1 . The intrinsic degradation rate constant of (2 R )- 5 was 0.405 ± 0.002 h –1 , which is approximately twice that of (2 S )- 5 (the k value was 0.226 ± 0.002 h –1 ) under physiological conditions (pH 7.40, 37 °C).

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Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice

Cited by 20 publications

References 50 publications

Safety Assessment of Acyl Glucuronides—A Simplified Paradigm

Safety Assessment of Acyl Glucuronides—A Simplified Paradigm

Reduced metabolic capacity in fast and slow skeletal muscle via oxidative stress and the energy‐sensing of AMPK/SIRT1 in malnutrition

Chemo-Enzymatic Synthesis, Structural and Stereochemical Characterization, and Intrinsic Degradation Kinetics of Diastereomers of 1-β-O-Acyl Glucuronides Derived from Racemic 2-{4-[(2-Methylprop-2-en-1-yl)amino]phenyl}propanoic Acid

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