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 3months 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.
Ohman
Inger
I
Department of Medicine, Solna, Clinical Pharmacology Unit, Karolinska Institutet, Stockholm, Sweden. inger.ohman@ki.se
Luef
Gerhard
G
Tomson
Torbjörn
T
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003267:Contraception; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D020719:Glucuronides / Q000652:urine; D006801:Humans; D000077213:Lamotrigine; D008875:Middle Aged; D011247:Pregnancy / Q000187:drug effects / Q000378:metabolism*; D014227:Triazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000927:Anticonvulsants; D020719:Glucuronides; D014227:Triazines; D000077213:Lamotrigine