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

Abstract

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.

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

“…Discrepancies vs . reported effects of these polymorphisms might be due to several factors, including rather limited/small sample sizes, differences in minor allele frequency or (not) accounting for confounding (genetic or other).…”

“…We were also unable to detect any relevant impact of UGT1A4*3 or UGT2B7 -161C>T on lamotrigine troughs, while UGT1A4*2 variant allele carriers were too few for any meaningful analysis. Discrepancies vs. reported effects of these polymorphisms [7][8][9][10][11][12]19] might be due to several factors, including rather limited/small sample sizes, differences in minor allele frequency or (not) accounting for confounding (genetic or other).…”

“…Reports on a potential role of UGT polymorphisms in lamotrigine disposition variability have been somewhat conflicting with uncertain clinical relevance. Chinese patients homozygous for the variant allele at UTG1A4*3 had higher lamotrigine serum levels associated with a greater efficacy , while in Northern European and Turkish patients variant homozygosity or variant allele carriage, respectively, were associated with lower lamotrigine concentrations. In Chinese children cotreated with lamotrigine and valproate, both higher and lower lamotrigine concentrations were reported associated with this polymorphism.…”

“…In Chinese children cotreated with lamotrigine and valproate, both higher and lower lamotrigine concentrations were reported associated with this polymorphism. Regarding other UGT polymorphisms, one study in Northern Europeans suggested a trend of increasing lamotrigine concentrations in variant allele carriers at UGT1A4*2 , while a study in Central‐Southern European subjects found no association between UGT1A4*2 and lamotrigine pharmacokinetics. Studies investigating the impact of polymorphisms on activity of UGT2B7 were largely focused on a nonsynonymous polymorphism 802C>T [ UGT2B7*2 (His268Tyr), rs7439366], which is rather frequent in different ethnic groups and is in a complete linkage disequilibrium with a promoter polymorphism UGT2B7 –161C>T .…”

Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring

“…Complementary pharmacogenetic testing may, however, elucidate the reason for unexpected relationships between dose and serum concentrations of certain AEDs when CYP2C9 and 2C19, and to some extent UGTs, are shown to have polymorphisms that may give rise to a poor metaboliser phenotype. Susceptible AEDs are clobazam, phenytoin, and to a lesser extent, lamotrigine (Lee et al, 2007;Gulcebi et al, 2011;Burns et al, 2016;Reimers et al, 2016). Genetic variability in drug transporters, as a mechanism for pharmacoresistance, is still under debate and needs further research (Löscher et al, 2009).…”