Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China

Chang, Ying; Yang, Liya; Zhang, Meng-chao; Liu, Songyan

doi:10.1007/s00228-014-1690-1

Cited by 55 publications

(50 citation statements)

References 22 publications

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“…Clearly, as the effect of *2 in our study was non-significant, this finding needs to be confirmed by others. With regard to our results on *3, decreases in drug serum concentrations have also been reported by others (Chan 2013;Chang et al 2014;Ghotbi et al 2010;Gulcebi et al 2011). Paradoxically, in the Chan study (2013), significantly lower LTG serum concentrations were found in heterozygous individuals (wild type/ *3), but not in homozygous individuals (*3/*3).…”

Section: Enzyme Inhibitorsupporting

confidence: 78%

“…High serum concentrations during treatment initiation with LTG are associated with a higher risk for severe cutaneous reactions and other adverse effects (Chang et al 2014;Guberman et al 1999). On the other hand, low drug serum concentrations may lead to insufficient therapeutic efficacy (Chang et al 2014). Polymorphisms in the coding region of the UGT1A4 gene may alter enzyme activity and thereby lead to reduced or enhanced elimination of LTG and, thus, altered serum concentrations.…”

Section: Discussionmentioning

confidence: 98%

“…Polymorphisms in the coding region of the UGT1A4 gene may alter enzyme activity and thereby lead to reduced or enhanced elimination of LTG and, thus, altered serum concentrations. Previous studies on the effects of two common SNPs of the UGT1A4 gene, *2 and *3, found both unchanged, reduced, and enhanced enzyme activity (Chang et al 2014;Ehmer et al 2004;Erickson-Ridout et al 2011, Under 12 years, n (%) 6 (3 %)…”

Section: Discussionmentioning

confidence: 98%

“…The available epidemiological data suggest highly variable frequencies of 0-8.8 % for the *2 allele and 3.5-22.5 % for *3, with considerable interethnic differences (Benoit-Biancamano et al 2009;Chang et al 2014;Gulcebi et al 2011;Kim et al 2006;Lopez et al 2013;Menard et al 2009;Saeki et al 2005;Thomas et al 2006). Therefore, we undertook the present study with the aim to generate more data on the frequency and the clinical relevance of the two UGT1A4 variants *2 and *3 for lamotrigine serum concentrations.…”

Section: Introductionmentioning

confidence: 92%

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Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine

Reimers

Sjursen

Helde

et al. 2014

Eur J Drug Metab Pharmacokinet

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The gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A4 shows considerable polymorphism. Several common drugs are metabolised by UGT1A4, among them lamotrigine (LTG). Experimental and clinical studies suggest that certain variants of UGT1A4 are associated with altered enzyme activity. However, results are conflicting. This clinical study aimed to investigate the frequencies of two common UGT1A4 variants, *2 (P24T) and *3 (L48V), and their potential effects on serum concentrations of LTG. The *2 variant was associated with a trend towards higher serum concentrations, while the *3 variant was associated with significantly lower serum concentrations of LTG. The calculated allele frequencies were in the same range as in earlier studies on Caucasian populations. To our knowledge, this is the first study suggesting a clinical effect of UGT1A4*2. Further study is needed to confirm this finding.

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Section: Enzyme Inhibitorsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 92%

See 2 more Smart Citations

Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine

Reimers

Sjursen

Helde

et al. 2014

Eur J Drug Metab Pharmacokinet

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“…Such a variation may lead to significant differences in the hepatic clearance of many AEDs [37], with increase or reduction in metabolic capacity resulting in different phenotypes [38]. Similarly, renal clearance can be affected by differences in the expression level of renal transporters [39,40].…”

Section: Clearance: Influence Of Genotype Size and Maturationmentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

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Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

Milosavljević,

Manojlović,

Matković

et al. 2024

JAMA Netw Open

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ImportancePrecise estimation of a patient’s drug metabolism capacity is important for antiseizure dose personalization.ObjectiveTo quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes.Data SourcesPubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions.Study SelectionTwo reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants.Data Extraction and SynthesisThe Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis.Main Outcomes and MeasuresPlasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant.ResultsData from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers.Conclusions and RelevanceThis systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

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Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China

Cited by 55 publications

References 22 publications

Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine

Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

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Correlation of the UGT1A4 gene polymorphism with serum concentration and therapeutic efficacy of lamotrigine in Han Chinese of Northern China

Cited by 55 publications

References 22 publications

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine

Frequencies of UGT1A4*2 (P24T) and *3 (L48V) and their effects on serum concentrations of lamotrigine

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

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Product

Resources

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Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine

Frequencies of UGT1A42 (P24T) and 3 (L48V) and their effects on serum concentrations of lamotrigine