Oral Contraceptives Induce Lamotrigine Metabolism: Evidence from a Double‐blind, Placebo‐controlled Trial

Christensen, Jakob; Petrenaite, Vaiva; Atterman, Jørn; Sidenius, Per; Öhman, Inger; Tomson, Torbjörn; Sabers, Anne

doi:10.1111/j.1528-1167.2007.00997.x

Cited by 147 publications

(89 citation statements)

References 16 publications

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“…A recent study reporting an increased ratio of lamotrigine glucuronide metabolite to lamotrigine concentration in pregnancy further supports increased glucuronidation of lamotrigine in pregnancy (Ohman et al, 2008). It is interesting to note that elimination of lamotrigine is similarly increased by use of oral contraceptives (Sabers et al, 2003;Christensen et al, 2007), especially estrogen-based contraceptives (Reimers et al, 2005). This finding suggests that estrogen may be involved in regulating the expression or function of UGT1A4 and/or UGT2B7.…”

mentioning

confidence: 71%

Up-Regulation of UDP-Glucuronosyltransferase (UGT) 1A4 by 17β-Estradiol: A Potential Mechanism of Increased Lamotrigine Elimination in Pregnancy

Chen¹,

Yang²,

Choi³

et al. 2009

Drug Metab Dispos

123

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ABSTRACT:Oral clearance of lamotrigine, an antiepileptic drug commonly used in pregnant women, is increased in pregnancy by unknown mechanisms. In this study, we show that 17␤-estradiol (E 2 ) upregulates expression of UDP glucuronosyltransferase (UGT) 1A4, the major enzyme responsible for elimination of lamotrigine. Endogenous mRNA expression levels of UGT1A4 in estrogen receptor (ER) ␣-negative HepG2 cells were induced 2.3-fold by E 2 treatment in the presence of ER␣ expression. E 2 enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ER␣ was cotransfected. Induction of UGT1A4 transcriptional activity by E 2 was also observed in ER␣-positive MCF7 cells, which was abrogated by pretreatment with the antiestrogen fulvestrant (ICI 182,780). Analysis of UGT1A4 upstream regions using luciferase reporter assays identified a putative specificity protein-1 (Sp1) binding site (؊1906 to ؊1901 base pairs) that is critical for the induction of UGT1A4 transcriptional activity by E 2 . Deletion of the Sp1 binding sequence abolished the UGT1A4 up-regulation by E 2 , and Sp1 bound to the putative Sp1 binding site as determined by a electrophoretic mobility shift assay. Analysis of ER␣ domains using ER␣ mutants revealed that the activation function (AF) 1 and AF2 domains but not the DNA binding domain of ER␣ are required for UGT1A4 induction by E 2 in HepG2 cells. Finally, E 2 treatment increased lamotrigine glucuronidation in ER␣-transfected HepG2 cells. Together, our data indicate that up-regulation of UGT1A4 expression by E 2 is mediated by both ER␣ and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.Human pregnancy is accompanied by various physiological changes, including a dramatic increase in the production of female hormones, i.e., estrogen and progesterone. Blood levels of these hormones rise up to 100-fold by term (Cunningham, 2005). At this high concentration, female hormones manifest functions different from those of their conventional role as gonadal hormones. As a result, various clinical symptoms associated with pregnancy occur, e.g., delayed gastric emptying or intrahepatic cholestasis. Clinical evidence suggests that pregnancy also alters the rate and extent of hepatic drug metabolism (Anderson, 2005;Hodge and Tracy, 2007). Hepatic metabolism is a major elimination route of drugs, and altered drug metabolism during pregnancy can lead to increased drug toxicity or decreased drug efficacy, adversely affecting both the mother and fetus. However, mechanisms underlying altered hepatic drug metabolism in pregnancy are poorly understood.Lamotrigine is widely prescribed for seizure control in women with child-bearing potential (Sabers et al., 2004;EURAP Study Group, 2006). Of clinical importance to its use during pregnancy, the apparent clearance of lamotrigine increases by 50 to 90% in pregnancy, requiring dosage adjustment to prevent exacerbation of seizures (de Haan et al., 2004;Harden, 2007;Pennell et al., 2008). La...

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confidence: 71%

Up-Regulation of UDP-Glucuronosyltransferase (UGT) 1A4 by 17β-Estradiol: A Potential Mechanism of Increased Lamotrigine Elimination in Pregnancy

Chen¹,

Yang²,

Choi³

et al. 2009

Drug Metab Dispos

123

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“…B. in hormonellen Kontrazeptiva) selbst schneller abgebaut [33], was als eine Folge der gesteigerten Aktivität der UDP-Glucuronosyltransferase 1A4 angesehen wird [34]. Eine Hormonbehandlung zur Kontrazeption oder Hormonersatztherapie erfordert eine Dosissteigerung von LTG um etwa 30-50 % innerhalb einer Woche nach Beginn der Hormongabe.…”

Section: Antikonvulsive Medikamente Und Steroidmetabolismusunclassified

Hormon- und Sexualstörungen bei Epilepsie

Luef

2018

Z. Epileptol.

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“…In combined oral contraceptives, during the period ''on the pill'' lamotrigine levels decrease by approximately 50%, followed by an increase of lamotrigine levels in the contraceptivefree week up to 80-100% of the baseline lamotrigine level. This is often clinically relevant and may result in an increased risk of seizure recurrence especially in week 2 and 3 on the pill or in concentration-dependent adverse effects at the end of the pill-free interval (Sabers www.intechopen.com Stodieck &Schwenkhagen, 2004;Christensen, 2007). These fluctuations are most likely due to an induction of UGT1A4, the enzyme responsible for the glucoronidation of lamotrigine, by EE.…”

Section: Contraception and Epilepsymentioning

confidence: 99%