Identification of a novel metabolite of vildagliptin in humans: Cysteine targets the nitrile moiety to form a thiazoline ring

Mizuno, Keita; Takeuchi, Kenji; Umehara, Ken; Nakajima, Miki

doi:10.1016/j.bcp.2018.08.043

Cited by 7 publications

(30 citation statements)

References 33 publications

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“…M20.7, a carboxylic acid metabolite of VG, is its major metabolite in humans and animals (He et al, 2009a,b;Asakura et al, 2015). M407 is a thiazoline acid metabolite formed via cysteine conjugation, which we identified previously (Mizuno et al, 2018). After administration of VG, M20.7 was detected in plasma at higher concentrations than VG (Fig.…”

Section: Plasma Pharmacokinetics and Excretions Of Vg And Itsmentioning

confidence: 76%

“…VG and its carboxylic acid metabolite (M20.7) were purchased from LKT Laboratories (St. Paul, MN) and Santa Cruz Biotechnology (Dallas, TX), respectively. M407 was previously synthesized (Mizuno et al, 2018). GSH was purchased from Nacalai Tesque (Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…The Orbitrap Fusion System was operated to obtain full-scan mass spectra and product-ion spectra over the range of m/z 100 to 1000 in electrospray-positive and electrospray-negative ionization modes. First, referring to previous reports (He et al, 2009b;Mizuno et al, 2018), exact ion chromatograms of [M+H] + and [M2H] 2 ions of VG and the identified metabolites (M15.3, M20.7, M20.2, and two types of mono-hydroxyl VG, M18.6, and M407) were obtained. When the specified mass peaks were detected on the exact ion chromatograms, the product-ion spectra were analyzed to confirm their chemical structures.…”

Section: Methodsmentioning

confidence: 99%

“…Dahal et al (2013) reported that radiolabeled VG binds to macromolecules in human hepatocytes in vitro, suggesting that VG can form covalent bonds. We recently found that VG binds covalently to the thiol residue of L-cysteine rather than to GSH (Mizuno et al, 2018). Structural analysis of the compound revealed that the nitrile moiety of VG is irreversibly converted to a thiazoline acid to form the VG-cysteine adduct M407 (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation

et al. 2019

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Vildagliptin (VG), a dipeptidyl peptidase-4 inhibitor, is used for treating type 2 diabetes. On rare occasions, VG causes liver injury as an adverse reaction. One case report suggested the involvement of immune responses in the hepatotoxicity, but the underlying mechanisms are unknown. We recently reported that VG binds covalently in vitro to L-cysteine to produce a thiazoline acid metabolite, M407, implying that the covalent binding may trigger the immune-mediated hepatotoxicity. There was no evidence, however, that such a thiazoline acid metabolite was formed in vivo. In the present study, we administered a single oral dose of VG to male Sprague-Dawley rats, and detected M407 in plasma. The sum of urinary and fecal excretions of M407 reached approximately 2% of the dose 48 hours postdosing. Using bile duct-cannulated rats, we demonstrated that M407 was secreted into bile as a glucuronide, designated as M583. Another newly identified thiazoline metabolite of VG, the cysteinylglycine conjugate M464, was detected in urine, feces, and bile. The formation of M464 was confirmed by in vitro incubation of VG with glutathione even in the absence of metabolic enzymes. A glutathione adduct against the nitrile moiety M611 was also detected in vitro but not in vivo. In summary, we found three new thiazoline-containing thiol adduct metabolites in VG-administered rats. Nonenzymatic covalent binding of VG would likely occur in humans, and it may be relevant to predicting adverse reactions.No potential conflicts of interest relevant to this article are reported.

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Section: Plasma Pharmacokinetics and Excretions Of Vg And Itsmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation

et al. 2019

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“…The study of drug metabolism plays a pivotal role in the drug discovery process (Ezzeldin et al, 2017;Godinho et al, 2018;Shankar et al, 2018), which is necessary to explore the metabolic fate thoroughly. The information regarding case reports associated with biotransformation and identification of metabolites will provide researchers with a better understanding about the activity and risks of trepibutone (Huskey et al, 2016; Iegre et al, 2016; Aras et al, 2017; Glaenzel et al, 2018; He and Wan, 2018; Mizuno et al, 2018). Hence, explicit metabolite profiles and metabolic pathways are essential for further research (Isin et al, 2012; Pozo et al, 2015; Xing et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers

Sun¹,

Yang²,

Liu³

et al. 2019

Front. Pharmacol.

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Trepibutone was widely used for cholelithiasis, cholecystitis, biliary tract dyskinesia, cholecystectomy syndrome, and chronic pancreatitis in clinic. However, few investigations on trepibutone have been conducted. In this study, an accurate, sensitive, and selective analytical method was developed and successfully applied to assess the pharmacokinetic behavior of trepibutone in rats. Trepibutone and carbamazepine (internal standard, IS) were quantified using multiple reaction monitoring (MRM) mode with the transitions of m/z 311.09→265.08 and m/z 237.06→194.08, respectively. The linearity, precision, accuracy, extraction recovery, matrix effect, and stability of the established method were all excellent within acceptable range. A total of 30 metabolites were identified in plasma and urine by Q-Exactive high resolution mass spectrometry, and several common metabolic pathways were observed such as dealkylation, oxidation, reduction, glucuronidation, and so on. This research provides more information on trepibutone in pharmacodynamics and toxicology and will assist the usage of trepibutone in clinical.

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Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts

Wang,

Tuohy,

et al. 2024

Adv Healthcare Materials

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Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels were engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels were formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds were introduced between the thiolated hyaluronic acid and nitrile‐containing baricitinib for drug tethering, which was confirmed with 1H and 13C nuclear magnetic resonance (NMR). Release of baricitinib was tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls were injected intradermally into an imiquimod‐induced mouse model of psoriasis. Imiquimod increased epidermal thickness in mice, which was unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppressed the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib was important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.This article is protected by copyright. All rights reserved

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Identification of a novel metabolite of vildagliptin in humans: Cysteine targets the nitrile moiety to form a thiazoline ring

Cited by 7 publications

References 33 publications

Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation

Identification of Novel Metabolites of Vildagliptin in Rats: Thiazoline-Containing Thiol Adducts Formed via Cysteine or Glutathione Conjugation

Pharmacokinetics and Metabolite Profiling of Trepibutone in Rats Using Ultra-High Performance Liquid Chromatography Combined With Hybrid Quadrupole-Orbitrap and Triple Quadrupole Mass Spectrometers

Local and Sustained Baricitinib Delivery to the Skin through Injectable Hydrogels Containing Reversible Thioimidate Adducts

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