Mexiletine carbonyloxy β-D-glucuronide: a novel metabolite in human urine

Senda, Chiaki; Toda, S; Tateishi, Mitsuru; Kobayashi, Kaoru; Igarashi, Takashi; Chiba, Kazuhiro

doi:10.1080/0049825031000140904

Cited by 10 publications

(9 citation statements)

References 17 publications

(15 reference statements)

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“…An ethyl carbamate reference compound was also synthesized readily by reacting the parent amine-containing compound with ethylchloroformate. Senda and coworkers [33] described a similar derivatization method using sodium methoxide. Depending on the structure of the drug portion of the conjugate, treatment with base can lead to rearrangement reactions as described above for tocainide [49] and carvedilol [50].…”

Section: Methods Of Analysismentioning

confidence: 98%

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Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

Schaefer¹

2006

CDM

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Glucuronidation is an important mechanism used by mammalian systems to clear and eliminate both endogenous and foreign chemicals. Many functional groups are susceptible to conjugation with glucuronic acid, including hydroxyls, phenols, carboxyls, activated carbons, thiols, amines, and selenium. Primary and secondary amines can also react with carbon dioxide (CO(2)) via a reversible reaction to form a carbamic acid. The carbamic acid is also a substrate for glucuronidation and results in a stable carbamate glucuronide metabolite. The detection and characterization of these products has been facilitated greatly by the advent of soft ionization mass spectrometry techniques and high field NMR instrumentation. The formation of carbamate glucuronide metabolites has been described for numerous pharmaceuticals and they have been identified in all of the species commonly used in drug metabolism studies (rat, dog, mouse, rabbit, guinea pig, and human). There has been no obvious species specificity for their formation and no preference for 1 degrees or 2 degrees amines. Many biological reactions have also been described in the literature that involve the reaction of CO(2) with amino groups of biomolecules. For example, CO(2) generated from cellular respiration is expired in part through the reversible formation of a carbamate between CO(2) and the alpha-amino groups of the alpha- and beta-chains of hemoglobin. Also, carbamic acid products of several amines, such as beta-N-methylamino-L-alanine (BMAA), ethylenediamine, and L-cysteine have been implicated in toxicity. Studies suggested that a significant portion of amino-compounds in biological samples (that naturally contain CO(2)/bicarbonate) can be present as a carbamic acid.

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Section: Methods Of Analysismentioning

confidence: 98%

“…[32]. Mexiletine, a close structural analogue of tocainide, also formed a carbamate glucuronide that accounted for approximately 25% of the administered dose [33].…”

Section: Some Of the Compounds Shown Inmentioning

confidence: 99%

Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

Schaefer¹

2006

CDM

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“…In healthy human subjects, approximately 25 to 40% of administered tocainide was excreted as the CG in urine (Gipple et al, 1982). Approximately 30% of administered mexiletine was excreted as a CG in human urine (Senda et al, 2003). Species differences in the formation of various CGs have been reported (Elvin et al, 1980;Gipple et al, 1982;Beconi et al, 2003).…”

mentioning

confidence: 99%

Species Differences in the Formation of Vabicaserin Carbamoyl Glucuronide

Zheng¹,

Chandrasekaran²,

DeMaio³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Vabicaserin is a potent 5-hydroxtryptamine 2C full agonist with therapeutic potential for a wide array of psychiatric disorders. Metabolite profiles indicated that vabicaserin was extensively metabolized via carbamoyl glucuronidation after oral administration in humans. In the present study, the differences in the extent of vabicaserin carbamoyl glucuronide (CG) formation in humans and in animals used for safety assessment were investigated. After oral dosing, the systemic exposure ratios of CG to vabicaserin were approximately 12 and up to 29 in monkeys and humans, respectively, and the ratios of CG to vabicaserin were approximately 1.5 and 1.7 in mice and dogs, respectively. These differences in systemic levels of CG are likely related to species differences in the rate and extent of CG formation and elimination. Whereas CG was the predominant circulating metabolite in humans and a major metabolite in mice, dogs, and monkeys, it was a relatively minor metabolite in rats, in which oxidative metabolism was the major metabolic pathway. Although the CG was not detected in plasma or urine of rats, approximately 5% of the dose was excreted in bile as CG in the 24-h collection postdose, indicating the rat had the metabolic capability of producing the CG. In vitro, in a CO 2 -enriched environment, the CG was the predominant metabolite in dog and human liver microsomes, a major metabolite in monkey and mice, and only a very minor metabolite in rats. Carbamoyl glucuronidation and hydroxylation had similar contributions to vabicaserin metabolism in mouse and monkey liver microsomes. However, only trace amounts of CG were formed in rat liver microsomes, and other metabolites were more prominent than the CG. In conclusion, significant differences in the extent of formation of the CG were observed among the various species examined. The exposure ratios of CG to vabicaserin were highest in humans, followed by monkeys, then mice and dogs, and lowest in rats, and the in vitro metabolite profiles generally correlated well with the in vivo metabolites.Vabicaserin is a potent 5-hydroxtryptamine 2C (5-HT 2C ) full agonist and shows in vitro functional selectivity for 5-HT 2C over 5-hydroxtryptamine 2A (5-HT 2A ) and 5-hydroxtryptamine 2B (5-HT 2B ) receptors . Vabicaserin is effective in several animal models that are predictive of antipsychotic activity, with an atypical antipsychotic profile (Marquis et al., 2006). Administration of vabicaserin decreases nucleus accumbens dopamine without affecting striatal dopamine, which indicates mesolimbic selectivity (Marquis et al., 2006;Wacker and Miller, 2008). This profile is consistent with potential efficacy in the treatment of the psychotic symptoms of schizophrenia with decreased liability for extrapyramidal side effects. In addition, long-term administration of vabicaserin significantly decreases the number of spontaneously active mesocorticolimbic dopamine neurons without affecting nigrostriatal dopamine neurons (Marquis et al., 2006), consistent with the effects of atypi...

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“…easily fragment first by the loss of 176 Da and then by the loss of CO 2 . In the negative ion mode, a product ion at m/z 193 can be observed [99], just like in the case of acyl glucuronides. Interestingly, they can also fragment first by the loss of CO 2 , as reported for a carbamoylglucuronide of carvedilol [80] and benzyl and tbutyl carbamate ester derivatives of glutathione conjugates [100] in fast atom bombardment (FAB)-MS/MS analysis.…”

Section: Qualitative Analysis By Lc-ms/msmentioning

confidence: 94%

Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

Ketola¹,

Hakala

2010

CDM

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Glucuronidation is one of the main phase II metabolic reactions in humans and animals. A variety of analytical techniques and methods have been used for the detection and quantification of glucuronides of both endogenous and xenobiotic compounds from different biological samples of humans and animals. Drug metabolism has been extensively studied with both in vitro and in vivo experiments under various conditions. The purpose of this review is to explore in detail the benefits and drawbacks of different liquid chromatography-mass spectrometric (LC/MS) methods and techniques in detection and identification of all forms of glucuronide conjugates from in vitro, biological, and environmental samples. The entire analytical procedure is covered, from sample treatment, separation, and ionization to qualitative and quantitative analyses. The aim of this review is not to cover every published paper where glucuronides are identified and/or quantified, but rather to focus on special cases where a new analytical approach or technical development has led to a better, more specific, or more comprehensive detection, identification, or quantitation of glucuronide conjugates.

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Mexiletine carbonyloxy β-D-glucuronide: a novel metabolite in human urine

Cited by 10 publications

References 17 publications

Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

Reaction of Primary and Secondary Amines to Form Carbamic Acid Glucuronides

Species Differences in the Formation of Vabicaserin Carbamoyl Glucuronide

Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

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