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



We 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.



With a base model absorption rate (interindividual variability) was estimated at 1.96 h(-1) (72.8%), oral clearance at 2.32 l h(-1) (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).



Variability 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.
Faculty of Pharmacy, University of Ljubljana, 1000, Ljubljana.
Daniela
D
Milosheska
Department of Neurology, University Medical Centre Ljubljana, 1000, Ljubljana.
Bogdan
B
Lorber
Faculty of Pharmacy, University of Ljubljana, 1000, Ljubljana.
Tomaž
T
Vovk
Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, 1000, Ljubljana, Slovenia.
Matej
M
Kastelic
Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, 1000, Ljubljana, Slovenia.
Vita
V
Dolžan
Faculty of Pharmacy, University of Ljubljana, 1000, Ljubljana.
Iztok
I
Grabnar
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D027702:Organic Cation Transporter 1 / Q000235:genetics; D011446:Prospective Studies; D014018:Tissue Distribution; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000927:Anticonvulsants; D027702:Organic Cation Transporter 1; D014227:Triazines; C074259:lamotrigine 2-N-glucuronide; D014453:Glucuronosyltransferase; D000077213:Lamotrigine
epilepsy; lamotrigine; metabolism; pharmacogenetics; population pharmacokinetics