Metabolism of Lamotrigine to a Reactive Arene Oxide Intermediate

Maggs, James L.; Naisbitt, Dean J.; Tettey, J.N.A.; Pirmohamed, Munir; Park, B K

doi:10.1021/tx0000825

Cited by 103 publications

(66 citation statements)

References 32 publications

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“…The major drugrelated components detected in control mouse urine were the parent lamotrigine and lamotrigine N-oxide, as reported earlier in rats ( Fig. 2B; (Parsons and Miles, 1984;Maggs et al, 2000). The small amounts of radioactivity excreted in the bile of both chimeric and control mice were comprised largely of unchanged lamotrigine (data not shown).…”

Section: Resultssupporting

confidence: 82%

“…Similar to many other tertiary amine drugs that form quaternary ammonium glucuronides, formation of the lamotrigine N-2 glucuronide appears to be restricted to monkeys and humans and is not observed to a significant extent in rodents (Green et al, 1995;Luo et al, 1995;Hawes, 1998). In rats, lamotrigine is eliminated largely via urinary excretion of the intact parent drug and, to a lesser extent, via N-2-oxidation (to form an N-oxide) and sequential epoxidation and glutathione conjugation of the O-dichlorophenyl ring (Parsons and Miles, 1984;Maggs et al, 2000). This species difference in the formation of quaternary ammonium glucuronides appears related to the fact that this metabolic pathway is catalyzed by the UGT1A4 enzyme, which is a pseudogene in rodents (Green et al, 1995;Green and Tephly, 1998;Ogura et al, 2006;Argikar et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Application of Chimeric Mice with Humanized Liver for Study of Human-Specific Drug Metabolism

et al. 2014

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Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

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Section: Resultssupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Application of Chimeric Mice with Humanized Liver for Study of Human-Specific Drug Metabolism

et al. 2014

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“…A previous study found convincing evidence of a glutathione conjugate of lamotrigine in rat bile, which was presumed to be formed from a reactive arene oxide (Maggs et al, 2000). However, no phenol metabolites were detected in humans (Doig and Clare, 1991), and in general phenols are one of the major downstream products of arene oxides.…”

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confidence: 95%

“…The symptoms can include fever, skin rash, agranulocytosis, and lymphadenopathy (Schlienger et al, 1998). There appears to be an association between the formation of reactive metabolites and the risk that a drug will cause idiosyncratic drug reactions (Maggs et al, 2000). The two major hypotheses that have been used to link the formation of reactive metabolites and idiosyncratic drug reactions are the hapten hypothesis and the danger hypothesis (Uetrecht, 1999).…”

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confidence: 99%

Possible Bioactivation Pathways of Lamotrigine

Lu¹,

Uetrecht²

2007

Drug Metab Dispos

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ABSTRACT:The anticonvulsant lamotrigine is associated with idiosyncratic drug reactions, especially skin rashes. Most idiosyncratic reactions are believed to be caused by reactive metabolites. Previous studies have found evidence that an arene oxide is formed in rats; however, when we incubated radiolabeled lamotrigine with rat liver microsomes virtually no covalent binding was detected, and the expected downstream phenolic metabolites are not observed in humans. Rare cases of agranulocytosis have been associated with lamotrigine therapy, and we found that lamotrigine is oxidized to two different N-chloro products by HOCl. The more reactive Nchloro metabolite forms an adduct with N-acetylhistidine, and covalent binding was observed when radiolabeled lamotrigine was incubated with myeloperoxidase/H 2 O 2 /Cl ؊ . Another lamotrigine metabolite is an N-oxide. If this N-oxide were sulfated, it might be sufficiently reactive to bind to protein. The synthetic N-sulfate reacted with N-acetylserine; however, no covalent binding was detected when the radiolabeled N-oxide was incubated with sulfotransferase. We also investigated the possibility that lamotrigine might be oxidized to a free radical by other peroxidases or oxidized by other enzymes such as prostaglandin H synthase or tyrosinase, but no evidence of oxidation was found, and lamotrigine did not cause any detectable increase in lipid peroxidation in vivo. In view of the virtual lack of covalent binding to hepatic microsomes and the lack of any other likely pathway leading to metabolic activation in the skin, it is possible that the parent drug rather than a reactive metabolite causes lamotrigine-induced skin rashes.

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“…For example, in the rat, lamotrigine, a drug used in the management of epilepsy syndromes, was metabolized primarily by thioether addition to a reactive intermediate arene oxide, yielding the glutathione conjugate of dihydrohydroxylamotrigine. Unlike the DHSG conjugate of MK-0767, the DHSG conjugate of lamotrigine is unstable and spontaneously dehydrates and rearomatizes at room temperature or upon freezing and thawing (Maggs et al, 2000). Similarly, 1,2-dichlorobenzene was metabolized to dichlorocyclohexadiene epoxide, which underwent glutathione addition followed by the spontaneous loss of water to generate the glutathione conjugate of dichlorobenzene (Hissink et al, 1996).…”

Section: Downloaded Frommentioning

confidence: 99%

IDENTIFICATION AND METABOLISM OF A NOVEL DIHYDROHYDROXY-S-GLUTATHIONYL CONJUGATE OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST, MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], IN RATS

Reddy¹,

Doss

Creighton³

et al. 2004

Drug Metab Dispos

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MK-0767 [(؎)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide] is a novel thiazolidinedione-containing peroxisome proliferator-activated receptorMK-0767 is a thiazolidinedione (TZD)-containing drug that is a dual PPAR ␣/␥ agonist being investigated for the treatment of type 2 diabetes and dyslipidemia. Drugs of this class, designated as glitazones, can bind to PPAR (␣, ␥, or ␦) receptors in tissues, resulting in the increased expression of genes encoding proteins that are involved in glucose and lipid metabolism (Mudaliar and Henry, 2001).The in vitro and in vivo metabolism of MK-0767 has been studied extensively in rats, dogs, monkeys, and humans ( S. Vincent, M. Creighton, C. Kochansky, B. Karanam, and R. Franklin, unpublished results; Karanam et al., 2004;Liu et al., 2004), and its metabolism was qualitatively similar across the species. The major biotransformation pathway involved the scission of the TZD ring followed by S-methylation to form the methyl mercapto derivative, which was subsequently oxidized to the methyl sulfoxide and methyl sulfone metabolites . Following i.v. or p.o. administration of a single dose of MK-0767 to rats, dogs, and monkeys, the compound was eliminated mainly by way of metabolism followed by excretion of the metabolites into urine and feces via the bile (S. Vincent, M. Creighton, C. Kochansky, B. Karanam, and R. Franklin, unpublished results). It was observed, however, that the metabolite profiles in rat bile were different from those in feces from intact rats. The metabolite profile in bile was characterized by multiple polar entities as the major components, with trace amounts of intact parent. The metabolite profile in feces, on the other hand, was distinct in that it showed large amounts of the parent compound as well as the above-mentioned polar metabolites. Furthermore, incubation of the bile samples with intestinal contents generated metabolite profiles similar to the fecal profiles, suggesting that the polar components in bile were most likely conjugates of the parent compound as well as its metabolites (S. Vincent, M. Creighton, C. Kochansky, B. Karanam, and R. Franklin, unpublished results). The present study was undertaken to identify and characterize the polar metabolite(s) in rat bile, and it led to the identification of a novel dihydrohydroxy-S-glutathionyl (DHSG) conjugate of MK-0767. Such conjugates, formed by the nucleophilic addition of glutathione to an arene oxide intermediate, are generally unstable. In most cases, DHSG conjugates undergo dehydration to produce rearomatized glutathione conjugates. In the present study, the DHSG conjugate of MK-0767 was found to be stable, and it was isolated and characterized by LC-MS and 1 H NMR spectroscopic techniques. Furthermore, incubation of the isolated conjugate with rat intestinal contents produced the parent compound, suggesting a novel reduction by gut microflora. The mechanism of formation of the DHSG conjugate and its subsequent reduction to the parent comp...

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Metabolism of Lamotrigine to a Reactive Arene Oxide Intermediate

Cited by 103 publications

References 32 publications

Application of Chimeric Mice with Humanized Liver for Study of Human-Specific Drug Metabolism

Application of Chimeric Mice with Humanized Liver for Study of Human-Specific Drug Metabolism

Possible Bioactivation Pathways of Lamotrigine

IDENTIFICATION AND METABOLISM OF A NOVEL DIHYDROHYDROXY-S-GLUTATHIONYL CONJUGATE OF A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AGONIST, MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], IN RATS

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