{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:42:32Z","timestamp":1790710952607,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,5,29]],"date-time":"2016-05-29T00:00:00Z","timestamp":1464480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N\u20102\u2010glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for <jats:italic>UGT1A4<\/jats:italic>, <jats:italic>UGT2B7<\/jats:italic>, <jats:italic>ABCB1<\/jats:italic> and <jats:italic>SLC22A1<\/jats:italic>. Population pharmacokinetic analysis was performed by non\u2010linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent\u2013metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>With a base model absorption rate (interindividual variability) was estimated at 1.96\u00a0h<jats:sup>\u22121<\/jats:sup> (72.8%), oral clearance at 2.32\u00a0l\u00a0h<jats:sup>\u22121<\/jats:sup> (41.4%) and distribution volume at 77.6\u00a0l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co\u2010treatment with enzyme inducing or inhibiting drugs. In patients with <jats:italic>UGT2B7<\/jats:italic>\u2013161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with <jats:italic>UGT2B7<\/jats:italic> 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for <jats:italic>UGT2B7<\/jats:italic> may be useful in various clinical settings.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12984","type":"journal-article","created":{"date-parts":[[2016,4,20]],"date-time":"2016-04-20T20:58:25Z","timestamp":1461185905000},"page":"399-411","source":"Crossref","is-referenced-by-count":87,"title":["Pharmacokinetics of lamotrigine and its metabolite N\u20102\u2010glucuronide: Influence of polymorphism of UDP\u2010glucuronosyltransferases and drug transporters"],"prefix":"10.1111","volume":"82","author":[{"given":"Daniela","family":"Milosheska","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  1000 Ljubljana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Lorber","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Centre Ljubljana  1000 Ljubljana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toma\u017e","family":"Vovk","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  1000 Ljubljana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"Kastelic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry University of Ljubljana  1000 Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vita","family":"Dol\u017ean","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biochemistry University of Ljubljana  1000 Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iztok","family":"Grabnar","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Ljubljana  1000 Ljubljana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,5,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073897012001011"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1987.193"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000195888.51845.80"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073897012001041"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9673(01)88448-X"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.009340"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.08.032"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.12.032"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645110-00002"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01561.x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000076485.09353.7A"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/ane.12197"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.29"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2011.02.002"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181bd8295"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.026609"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.11.105"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2011.01.016"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1449-5"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1097\/FTD.0b013e3181ceecc6","article-title":"UGT2B7_\u2010161C\u00a0>\u00a0T polymorphism is associated with lamotrigine concentration\u2010to\u2010dose ratio in a multivariate study","volume":"32","author":"Blanca Sanchez M","year":"2010","journal-title":"Ther Drug Monit"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31826517c6"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dmpk.2014.12.007"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-014-1690-1"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/00912709922007949"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jssc.200700110"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2010.01.005"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(86)90046-2"},{"key":"e_1_2_9_29_1","volume-title":"NONMEM Users Guides. 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