Pharmacokinetics of lamotrigine and its metabolite N‐2‐glucuronide: Influence of polymorphism of UDP‐glucuronosyltransferases and drug transporters

Abstract

AIMSThis study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODSWe included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTSWith a base model absorption rate (interindividual variability) was estimated at 1.96 h À1 (72.8%), oral clearance at 2.32 l h À1 (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONSVariability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Interindividual variability in lamotrigine pharmacokinetics is large and therapeutic drug monitoring may be warranted.• Lamotrigine disposition is mediated by UDP-glucuronosyltransferases, mainly by UGT1A4 and UGT2B7. ABCB1 and SLC22A1 transporters appear to be also involved.• Polymorphisms in UGT1A4, UGT2B7, ABCB1 and SLC22A1 genes affect protein activity and expression. WHAT THIS STUDY ADDS• Influences of polymorphisms of UGT2B7, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs on lamotrigine pharmacokinetics were quantified.• No significant association of lamotrigine pharmacokinetics with UGT1A4, SLC22A1 and ABCB1 polymorphisms was observed.• Clearance of lamotrigine-N-2-glucuronide depends on renal function and body weight.

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

“…The latter has been suggested to affect the UGT2B7 transcription resulting in an increased glucuronidation activity for morphine and was also reported associated with valproate concentrations in epilepsy patients . In Central‐Southern European subjects , variant allele carriage at UGT2B7 –161C>T was associated with a 20% lower lamotrigine clearance, which is similar to results in Spanish and Thai patients .…”

“…In vitro studies suggest that lamotrigine is a substrate for ABCB1 transporter . We found an association between a variant allele at MDR1/ABCB1 1236C>T and lower lamotrigine troughs , while a lack of effect of this polymorphism on lamotrigine pharmacokinetics was also reported . One in vitro study excluded lamotrigine as a potential ABCG2 transporter substrate , but a subsequent one identified it as a substrate for human ABCG2 at therapeutic concentrations .…”

“…In this respect, the present study has several limitations: first, it was based on morning trough concentrations as a part of routine TDM and not on a detailed pharmacokinetic evaluation. This, however, does not diminish its potential clinical relevance, since morning troughs are recommended indicators in TDM of AEDs ; next, certain treatment‐by‐variant allele carriage subsets were rather small – there were only six (2.9%) variant allele carriers at UGT1A4*2 70C>A , precluding any meaningful analysis; finally, some other potentially interesting polymorphisms such as UGT2B7 372A>G , and UGT1A4 –219C>T / 163G>A were not considered. The present results should be viewed within the scope of these limitations.…”

“…Several AEDs and non‐AEDs strongly induce glucuronidation of lamotrigine and may reduce its efficacy, but the most profound is the effect of a glucuronidation inhibitor valproic acid . Polymorphisms of UGT enzymes, most commonly UGT1A4*3 , UGT1A4*2 and UGT2B7 –161C>T have also been investigated as potential sources of lamotrigine variability, but data have been rather sparse and contradictory . In vitro , lamotrigine is a substrate for MDR1/ABCB1 and ABCG2 transporters and sporadic studies have suggested that MDR1/ABCB1 exon 12 1236C>T polymorphism might be associated with somewhat lower lamotrigine troughs or have no effect on lamotrigine pharmacokinetics in Southern‐Central European adult patients, while ABCG2 421C>A polymorphism appeared associated with somewhat lower or higher concentrations in Chinese patients.…”

“…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 .…”