Meta‐analysis of the Influence of UGT Genetic Polymorphisms on Lamotrigine Concentration

Abstract

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are involved in the metabolism of lamotrigine, but whether the UGT1A4 and UGT2B7 genetic polymorphisms affect lamotrigine concentration remains controversial. Thus, the objective of this meta-analysis was to analyse the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration. Through searching, screening, selection, data extraction and quantitative analyses, the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration-to-dose ratio (CDR) was assessed by meta-analysis of nine studies. Neither UGT1A4 70C>A nor 142T>G significantly affected lamotrigine CDR values (standardized difference in means [SDM] = 0.433, 95% confidence interval [CI] = -0.380-1.302; SDM = -0.458, 95% CI = -1.141-0.224, respectively). Only the UGT2B7 -161C>T homozygous variant had significantly higher CDR values than the wild-type (WT) and heterozygous variant (SDM = 0.634, 95% CI = 0.056-1.222). In conclusion, CDR of lamotrigine was significantly higher for the UGT2B7 -161C>T homozygous variant than for the WT and heterozygous variant. Thus, UGT2B7 -161C>T homozygous variant needs to receive reduced dose.

Dosage Optimization of Lamotrigine in Pregnancy: A Pharmacometric Approach Using Modeling and Simulation

“…22 Also, a meta-analysis to evaluate the influence of UGT polymorphism on lamotrigine revealed that there is no significant influence of the main metabolizing enzyme UGT1A4 polymorphism on lamotrigine plasma levels. 29 It is also significant to bear in mind that During the third trimester, a decrease in the lamotrigine concentration-to-dose ratio (C/D ratio) was seen in all genotype panels and varied between 53% and 74%…”

“…Moreover, the study used gestational week as a covariate for the clearance model, which is a better predictor of changes in plasma concentrations of lamotrigine, possibly encompassing other contributing factors, compared with other covariates, and was favored by GOF plots and bootstrap analysis 22 . Also, a meta‐analysis to evaluate the influence of UGT polymorphism on lamotrigine revealed that there is no significant influence of the main metabolizing enzyme UGT1A4 polymorphism on lamotrigine plasma levels 29 . It is also significant to bear in mind that gestational age is simpler to attain in clinical settings and permits a straightforward clinical application of the model, whereas parameters like estrogen levels and genotyping are more challenging to obtain.…”

A repository of protein abundance data of drug metabolizing enzymes and transporters for applications in physiologically based pharmacokinetic (PBPK) modelling and simulation

“…4 and Table 3). The high inter-individual variability of this particular DME has been held responsible for adverse effects of lamotrigine, such as benign rashes, gastrointestinal disturbances and multi-organ failure associated with Steven Johnson syndrome 44,45 . In other reports, the reason for the observed variability has been attributed to underlying factors, such as age, gender, weight, co-medication, and state of renal and hepatic function 46–50 , highlighting the possibility of population effects.…”

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs

“…Subsequently, several meta-analyses [2][3][4][5][6][7][8][9][10][11][12] have attempted to address the problem of insufficient power by pooling data from published reports on the most promising associations between pharmacogenetic variants and variations in antiseizure drug concentrations. However, a critical review shows that many of these meta-analyses either used inappropriate methods or included only subsets of all available studies (Table 1).…”