Lamotrigine and Oral Contraceptives

Lamotrigine is widely used as an antiepileptic drug in the treatment of newly onset as well as refractory epilepsy (1;2). Lamotrigine is unique among the antiepileptic drug since the major route (76%) of elimination is conjugation with glucuronic acid (glucuronidation) (3). This conjugation reaction is catalyzed by the uridine 5'-diphosphate (UDP)-glucuronosyltransferases (UGTs); of which the isoform UGT1A4 probably is the major route of metabolism in humans (3). The pathway is inhibited by valproate and induced by other anticonvulsants (3), and explains the effect of these drugs on lamotrgine metabolism (4). Other drugs that are metabolized via direct glucoronidation may interfere with the metabolism of lamotrigine e.g. acetaminophen (5). Estrogeneous substrates are metabolized via glucuronidation (6-8) and may potentially interact with the metabolism of lamotrigine. In the development of lamotrigine for use in epilepsy patients the effect on the oral contraceptive pill was studied. In contrast to other commonly used antiepileptic drugs e.g. carbamazepine and phenytoin(9), lamotrigine did not significantly influence the constituents of the oral contraceptive pill (10-12). In addition, it was initially assumed from population pharmacokinetic studies, that oral contraceptives did not influence the metabolism of lamotrigine (13).However, recent retrospective studies indicate that oral contraceptives may increase the metabolism of lamotrigine resulting in a significant decrease in plasma concentration of lamotrigine when given with oral contraceptives (14;15). This effect is probably related to the ethinyl estradiol content of the combined contracetive pill and no the progesterone content (16).

To confirm and further extend these findings, the present study evaluates the effect of oral contraceptives on lamotrigine plasma concentrations in a double blind, placebo controlled, cross-over study in patients with epilepsy.

Reference List

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2. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL et al. Efficacy and Tolerability of the New Antiepileptic Drugs, I: Treatment of New-Onset Epilepsy: Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004; 45(5):401-409.

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8. Ebner T, Remmel RP, Burchell B. Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol. Mol Pharmacol 1993; 43(4):649-654.

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11. Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 2003 Apr ;44 (4 ):540 -9 44(4):540-549.

12. Holdish T, Whiteman P, Orme M, Back D, Ward S. Effect of lamotrigine on the pharmacology of the combined oral contraceptive pill. Epilepsia 32[suppl. 1], s96. 1991.

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14. Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology 2003 Aug 26 ;61 (4 ):570 -1 2003; 61(4):570-571.

15. Sabers A, Buchholt JM, ULDALL P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001 Nov ;47 (1 -2 ):151 -4 47(1-2):151-154.

16. Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia 2005; 46(9):1414-1417.