Acyl glucuronide reactivity in perspective

Bradshaw, Peter R.; Athersuch, Toby J.; Stachulski, Andrew V.; Wilson, Ian D.

doi:10.1016/j.drudis.2020.07.009

Cited by 25 publications

(17 citation statements)

References 60 publications

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“…M5/2 is most likely the result of acyl migration of M5, which is associated with acyl glucuronide reactivity. Acyl glucuronide intermediates are potential reactive intermediates that may cause unexpected side effects (Boelstarli 2002;Bradshaw et al, 2020), although no abnormal clinical significance or adverse events occurred in the current clinical trial.…”

Section: Discussionmentioning

confidence: 88%

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

et al. 2021

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HR011303, a promising selective URAT1 inhibitor, is currently being studied in a phase Ⅲ clinical trial in China for the treatment of hyperuricemia and gout. In the current study, the pharmacokinetics, mass balance, and metabolism of HR011303 were examined in six healthy Chinese male subjects who received a single oral dose of 10 mg of [ 14 C]HR011303 (80 µCi).The results showed that HR011303 was rapidly absorbed with a median T max = 1.50 h postdose, and the arithmetic mean t 1/2 of total radioactivity was approximately 24.2 h in plasma.The mean blood-to-plasma radioactivity concentration ratio was 0.66, suggesting the preferential distribution of drug-related components in plasma. At 216 h post-dose, the mean cumulative excreted radioactivity was 91.75% of the dose, including 81.50% in urine and 10.26% in feces. Six metabolites were identified, and the parent drug HR011303 was the most abundant component in plasma and feces, but a minor component in urine.Glucuronidation of the carboxylic acid moiety of HR011303 was the primary metabolic pathway in humans, amounting to 69.63% of the dose (M5, 51.57% of the dose; M5/2, 18.06% of the dose) in the urine; however, it was not detected in plasma. UGT2B7 was responsible for the formation of M5. Overall, after a single oral dose of 10 mg of [ 14 C]HR011303 (80 µCi), HR011303 and its main metabolites were eliminated via renal excretion. The major metabolic pathway was carboxylic acid glucuronidation, which was catalyzed predominantly by UGT2B7.

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Section: Discussionmentioning

confidence: 88%

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

et al. 2021

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“…The reactivity of acyl glucuronides has been the cause of concern, e.g ., refs − for many years because of their possible toxicity. As a result, there has been much research into methods for determining the stability of the 1- O -acyl glucuronides (and their transacylation rates), which have been used as surrogates for potential toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…However, in the case of acyl or ester, glucuronidation, an association between their production and drug toxicity, which has led in some instances to drug withdrawal, has been noted. In particular, this has been linked to the toxicity sometimes seen with nonsteroidal anti-inflammatory drugs (NSAIDs), many of which form acyl glucuronides (AGs) and a number of them have been withdrawn from the market due to adverse drug reactions (ADRs). − Such ADRs have led to regulatory authorities, such as the U.S. Federal Drug Administration, requiring efforts to be made in the toxicological assessment of these AGs. As a result, methods for determining their reactivity have been of increased interest to both medicinal chemists and toxicologists .…”

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confidence: 99%

“…One property that has been used for assessing the reactivity of acyl glucuronides, and therefore the potential risk posed by them, is the rate of transacylation in aqueous buffer of the biosynthetic 1-β- O -acyl-AG form to the 2-, 3-, and 4- O -acyl isomers. This degradation rate is used as a surrogate for reactivity with proteins. − Currently, the techniques most frequently used to determine transacylation rates for AGs are 1 H NMR spectroscopy, e.g ., ref , or high-performance liquid chromatography (HPLC) using either UV or MS detection ( e.g ., refs and ). However, analysis by either 1 H NMR spectroscopy or chromatographic methods is often time consuming.…”

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confidence: 99%

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Use of Cyclic Ion Mobility Spectrometry (cIM)-Mass Spectrometry to Study the Intramolecular Transacylation of Diclofenac Acyl Glucuronide

et al. 2021

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1-β-O-Acyl-glucuronides (AGs) are common metabolites of carboxylic acid-containing xenobiotics, including, e.g., many nonsteroidal anti-inflammatory drugs (NSAIDs). They are of concern to regulatory authorities because of the association of these metabolites with the hepatotoxicity that has resulted in drug withdrawal. One factor in assessing the potential risk posed by AGs is the rate of transacylation of the biosynthetic 1-β-O-acyl form to the 2-, 3-, and 4-O-acyl isomers. While transacylation can be measured using 1H NMR spectroscopy or liquid chromatography-mass spectrometry (LC-MS), the process can be time consuming and involve significant method development. The separation of these positional isomers by ion mobility spectrometry (IMS) has the potential to allow their rapid analysis, but conventional instruments lacked the resolving power to do this. Prediction of the collision cross section (CCS) using a machine learning model suggested that greater IMS resolution might be of use in this area. Cyclic IMS was evaluated for separating mixtures of isomeric AGs of diclofenac and was compared with a conventional ultraperformance liquid chromatography (UPLC)-MS method as a means for studying transacylation kinetics. The resolution of isomeric AGs was not seen using a conventional traveling wave IMS device; however, separation was seen after several passes around a cyclic IMS. The cyclic IMS enabled the degradation of the 1-β-O-acyl-isomer to be analyzed much more rapidly than by LC-MS. The ability of cyclic IMS to monitor the rate of AG transacylation at different pH values, without the need for a prior chromatographic separation, should allow high-throughput, real-time, monitoring of these types of reactions.

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“…Regarding the deleterious effects of the parent molecule, it has been proposed that glucuronide (TAK-875-Glu), one of the main metabolites of TAK-875, might accumulate aside TAK-875 in the liver, thus causing additional injuries. Glucuronides are considered to be under special attention in the mechanisms underlying DILI [ 50 ]. They may form reactive species through the opening of the ring and sharing atoms for covalent bonds with proteins and DNA ( Fig 11C ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

et al. 2021

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GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

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Acyl glucuronide reactivity in perspective

Cited by 25 publications

References 60 publications

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Use of Cyclic Ion Mobility Spectrometry (cIM)-Mass Spectrometry to Study the Intramolecular Transacylation of Diclofenac Acyl Glucuronide

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

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Acyl glucuronide reactivity in perspective

Cited by 25 publications

References 60 publications

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [14C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Use of Cyclic Ion Mobility Spectrometry (cIM)-Mass Spectrometry to Study the Intramolecular Transacylation of Diclofenac Acyl Glucuronide

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

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Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase

Pharmacokinetics, Mass Balance, and Metabolism of the Novel Urate Transporter 1 Inhibitor [¹⁴C]HR011303 in Humans: Metabolism Is Mediated Predominantly by UDP-Glucuronosyltransferase