Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

Autor: Yang J; Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Wang J; Department of Pharmacy, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Ning L; Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Wu C; Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Liu Y; Department of Pharmacy, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Xia J; Department of Pharmacy, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China., Guan Y; Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China. guanyp3@mail2.sysu.edu.cn., Liu Q; Department of Pharmacy, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China. qian159158@163.com., Zheng J; Department of Neurology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, 556000, Guizhou, China. 1418528797@qq.com.
Jazyk: angličtina
Zdroj: European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2024 Jul; Vol. 49 (4), pp. 437-447. Date of Electronic Publication: 2024 May 06.
DOI: 10.1007/s13318-024-00894-4
Abstrakt: Background and Objectives: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy.
Methods: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency.
Results: This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e -16 ). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 μg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 μg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 μg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively.
Conclusions: UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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