Effects of pregnancy and contraception on lamotrigine disposition:: New insights through analysis of lamotrigine metabolites

Objective: To investigate possible underlying mechanisms for alterations in lamotrigine (LTG) kinetics by gestation and use of contraceptives. Methods: Plasma concentrations of LTG and its main metabolite lamotrigine-2-N-glucuronide (2-N-GLUC) were measured in 31 women on LTG taking combined oral contraceptives (COC), in 12 with contraceptive intrauterine devices containing levonorgestrel (CIUD), and in 20 on LTG without hormonal contraception (controls). We also measured the levels of LTG and 2-N-GLUC in plasma and urine in eight women during pregnancy, and up to three months postpartum. LTG Levels in plasma were measured by high-performance liquid chromatography method (HPLC) and N-2-GLUC in urine and plasma and LTG in urine by liquid chromatography-mass spectrometry (LC/MS). Results: There were no significant differences in LTG dose/concentration (D/C), or N-2-GLUC/LTG ratios between women with CIUD and controls. In contrast, compared to controls, the LTG D/C ratio was 56% higher in women taking COC (mean +/- SD, 83 +/- 47 versus 53.0 +/- 24.2; p < 0.01) and N-2-GLUC/LTG ratio 82% higher in women taking COC (mean 0.477 +/- 0.212 SD versus 0.262 +/- 0.127; p < 0.0003. The 2-GLUC/LTG ratios were 154% higher in plasma and 122% higher in urine in late pregnancy compared with baseline 3 months postpartum. Conclusions: Our data indicate that the alterations in LTG kinetics in pregnancy as well as those induced by COC are mainly explained by enzymatic induction of the N-2-glucuronide pathway. In addition we found no evidence for an interaction between LTG and CIUD. (C) 2007 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.