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.

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Our findings suggest that the CAT c.-262C>T genetic polymorphism influences the susceptibility to alcohol dependence and severity of alcohol dependence, while CYP2E1 c.-1053C>T polymorphism influences the expression of obsessive-compulsive and anxiety symptoms.