UGT polymorphisms and lamotrigine clearance during pregnancy

• Published in: Epilepsy research 2018-02, Vol.140, p.199-208
• Main Authors: Petrenaite, Vaiva, Öhman, Inger, Ekström, Lena, Sæbye, Ditte, Hansen, Thomas Folkmann, Tomson, Torbjörn, Sabers, Anne
• Format: Article
• Language: English
• Subjects: Adult; Anticonvulsants - blood; Anticonvulsants - therapeutic use; Dose-Response Relationship, Drug; Epilepsy - blood; Epilepsy - drug therapy; Epilepsy - enzymology; Epilepsy - genetics; Female; Glucuronosyltransferase - genetics; Humans; Lamotrigine; Lamotrigine - blood; Lamotrigine - therapeutic use; Male; Medicin och hälsovetenskap; Pharmacogenomic Variants; Polymorphism; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Complications - blood; Pregnancy Complications - drug therapy; Pregnancy Complications - enzymology; Pregnancy Complications - genetics; Retrospective Studies; Sex Factors; Sex of foetus; UGT; Young Adult
• ISSN: 0920-1211; 1872-6844; 1872-6844
• DOI: 10.1016/j.eplepsyres.2018.01.011

•Genetic polymorphism of UGT1A4 T142G and UGT2B7 C802T influences LTG clearance changes during pregnancy and post-partum.•Homozygous carriers of UGT2B7 C802T had a more pronounced LTG clearance in the first and third trimester than heterozygous.•Multiple regression analysis showed a significant effect of female sex on LTG ratio changes at the end of pregnancy. To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP). Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus. Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between −53% and −74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: −53% (95%CI: −68% to −39%) versus −65% (95%CI: −69% to −60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were −64% in T2 (95%CI: −69% to −59%) and −67% in T3 (95%CI: −71% to −63%) in women who expected a female child compared to whose with a male child −58% in T2 (p = 0.002, 95%CI: −67% to −48%) and −57% in T3 (p