Studies on induction of lamotrigine metabolism in transgenic<i>UGT1</i>mice

Argikar, U. A.; Senekeo-Effenberger, Kathy; Larson, E. E.; Tukey, R. H.; Remmel, R. P.

doi:10.1080/00498250903188985

Cited by 6 publications

(7 citation statements)

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“…More importantly, the rate of ezetimibe glucuronide formation was not reduced in HLM samples genotyped as UGT1A1*28 compared with normal UGT1A1*1 HLMs, indicating that glucuronidation by UGT1A1 may not play a major role in overall ezetimibe metabolism. Because phenobarbital leads to the induction of UGT1A4 (Argikar et al, 2009) and we have observed significant induction of UGT1A3 and UGT1A9 and mild induction of UGT1A6 in Tg-UGT1 mice (Fig. 4), it is instead likely that ezetimibe conjugation is catalyzed by UGT2B proteins.…”

Section: Humanized Ugt1 Mice and Pharmacokinetic Predictionsmentioning

confidence: 77%

“…These similarities validate the use of humanized UGT1 mice to examine pharmacokinetic parameters in vivo, especially when substrates are selectively metabolized by UGT1A1. Recent experiments using transgenic UGT1 mice have been used successfully to examine the pharmacokinetic parameters of lamotrigine, a popular antiepileptic drug that is metabolized by human UGT1A4 (Argikar et al, 2009). With current human safety assessments of new drugs relying primarily on standard animal models and in vitro experiments, coupled with arguments that intrinsic clearance values that rely on in vitro microsomal metabolism studies underpredict in vivo clearance values by an order of magnitude (Miners et al, 2006), the introduction of humanized animals modeled to express drug and xenobiotic-metabolizing enzymes should be perceived as a valued addition (Cheung and Gonzalez, 2008) toward providing accurate information in predicting human drug metabolism.…”

Section: Humanized Ugt1 Mice and Pharmacokinetic Predictionsmentioning

confidence: 99%

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A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

Cai¹,

Nguyen²,

Peterkin³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Humanized mice that express the human UDP-glucuronosyltransferase (UGT) 1 locus have been developed in a Ugt1-null background as a model to improve predictions of human UGT1A-dependent drug clearance. Enzyme kinetic parameters (K m and V max ) and pharmacokinetic properties of three probe drugs were compared using wild-type and humanized UGT1 mice that express the Gilbert's UGT1A1*28 allele [Tg(UGT1

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Section: Humanized Ugt1 Mice and Pharmacokinetic Predictionsmentioning

confidence: 77%

Section: Humanized Ugt1 Mice and Pharmacokinetic Predictionsmentioning

confidence: 99%

A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

Cai¹,

Nguyen²,

Peterkin³

et al. 2010

Drug Metab Dispos

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“…Carbamazepine, clobazam, lamotrigine, levetiracetam, phenobarbital, and stiripentol in plasma samples were assayed by high performance liquid chromatography (HPLC) based on previously described methods with modifications . Details regarding sample preparation and chromatographic conditions for each drug are provided in Table S1 and Figure S2.…”

Section: Methodsmentioning

confidence: 99%

Screening of conventional anticonvulsants in a genetic mouse model of epilepsy

Hawkins

Anderson

Gertler

et al. 2017

Ann Clin Transl Neurol

102

210

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ObjectiveEpilepsy is a common neurological disorder that affects 1% of the population. Approximately, 30% of individuals with epilepsy are refractory to treatment, highlighting the need for novel therapies. Conventional anticonvulsant screening relies predominantly on induced seizure models. However, these models may not be etiologically relevant for genetic epilepsies. Mutations in SCN1A are a common cause of Dravet Syndrome, a severe epileptic encephalopathy. Dravet syndrome typically begins in infancy with seizures provoked by fever and then progresses to include afebrile pleomorphic seizure types. Affected children respond poorly to available anticonvulsants. Scn1a +/− heterozygous knockout mice recapitulate features of Dravet syndrome and provide a potential screening platform to investigate novel therapeutics. In this study, we conducted a screening of conventional anticonvulsants in Scn1a +/− mice to establish assays that most closely correlate with human response data.MethodsOn the basis of clinical response data from a large, single center, retrospective survey of Dravet syndrome case records, we selected nine drugs for screening in Scn1a +/− mice to determine which phenotypic measures correlate best with human therapeutic response. We evaluated several screening paradigms and incorporated pharmacokinetic monitoring to establish drug exposure levels.Results Scn1a +/− mice exhibited responses to anticonvulsant treatment similar to those observed clinically. Sodium channel blockers were not effective or exacerbated seizures in Scn1a +/− mice. Overall, clobazam was the most effective anticonvulsant in Scn1a +/− mice, consistent with its effect in Dravet syndrome.InterpretationGenetic models of spontaneous epilepsy provide alternative screening platforms and may augment the AED development process. In this study, we established an effective screening platform that pharmacologically validated Scn1a +/− mice for preclinical screening of potential Dravet syndrome therapeutics.

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“…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). Therefore, the extent of formation of this N-2 glucuronide in chimeric mice could serve as an indication of the humanization of the mouse liver in terms of UGT1A4 expression and activity.…”

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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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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Studies on induction of lamotrigine metabolism in transgenicUGT1mice

Cited by 6 publications

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A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

Screening of conventional anticonvulsants in a genetic mouse model of epilepsy

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

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Studies on induction of lamotrigine metabolism in transgenicUGT1mice

Cited by 6 publications

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A Humanized UGT1 Mouse Model Expressing the UGT1A1*28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

A Humanized UGT1 Mouse Model Expressing the UGT1A1*28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

Screening of conventional anticonvulsants in a genetic mouse model of epilepsy

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

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A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation

A Humanized UGT1 Mouse Model Expressing the *UGT1A1**28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation