Plasma concentrations of lamotrigine and its 2‐N‐glucuronide metabolite during pregnancy in women with epilepsy

Öhman, Inger; Beck, Olof; Vitols, Sigurd; Tomson, Torbjörn

doi:10.1111/j.1528-1167.2007.01471.x

Cited by 96 publications

(81 citation statements)

References 21 publications

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“…The intermediate level of plasma protein binding of lamotrigine (ϳ50%) suggests a minor role of protein binding, but a significant role of intrinsic hepatic enzyme activity, in causing the increase in oral clearance in pregnancy. 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…”

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confidence: 99%

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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mentioning

confidence: 99%

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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“…Compared with other AEDs used as monotherapy, women exposed to lamotrigine monotherapy in pregnancy were more likely to have deterioration in seizure control from the first to the second or third trimesters and more generalized tonic-clonic seizures (GTCS) potentially related to reduced drug levels. [28][29][30][31] The other possibility is that lamotrigine for some women is inferior to other AEDs (especially valproate) in controlling GTCS. These would suggest the possibility that lamotrigine may be associated with epilepsy-related death in and around pregnancy; however, conversely, there appears not to have been any consistent increase in such deaths in parallel with the increasing use of the drug.…”

Section: Discussionmentioning

confidence: 99%

Trends in maternal deaths from epilepsy in the United Kingdom: a 30-year retrospective review

Kapoor

Wallace

2014

Obstet Med

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Objective: Neurological diseases remain the second most common cause of maternal mortality from indirect causes, according to the last United Kingdom confidential enquiry into maternal death. The maternal mortality rate from epilepsy is reported as 0.61 per 100,000 maternities. The aim of this study was to analyse the trends and causes of maternal death from epilepsy in the UK over the last 30 years. Information on sub-standard care associated with fatalities was also consolidated to inform guidance and clinical care by obstetricians and physicians caring for pregnant women with epilepsy.Study design: A retrospective review of 10 triennial confidential enquiry into maternal death reports was performed, encompassing 21,514,457 maternities. Late and coincidental deaths were not included in the analyses.Results: Between 1979 and 2008, there were 92 maternal deaths from epilepsy. The proportion of total maternal deaths from epilepsy over 30 years is 3.7% (95% CI 3.0-4.5), which showed an increasing trend. Sudden unexpected death in epilepsy remains the single greatest cause of maternal death from epilepsy followed by aspiration of gastric contents during seizures and drowning during bathing.Conclusion: All women with epilepsy should be looked after by specialist combined obstetric and medical or neurological teams in pregnancy to improve maternal and fetal outcomes.

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“…Az előzetes eredmények azt mutatják, hogy más epilepszia-tünetegyüttesekben -beleértve az idiopathiás generalizált epilepsziákat is -hatékony [27].…”

Section: Levetiracetamunclassified

Epilepsziával szövődött terhesség preconceptionalis és perinatalis kihívásai

et al. 2016

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Reproduktív korú, epilepsziában szenvedő nőknél számos speciális probléma jelentkezhet a mindennapi klinikai gyakorlatban. Az epilepsziás görcsrohamoknak a szülés kimenetelére való hatása, valamint az alkalmazott antiepileptikus terápia teratogén kockázatának minimálisra csökkentése gondos odafigyelést és együttműködést igényel a szülész-nőgyógyász és neurológus részéről. A szerzők áttekintik a görcsrohamok magzatra gyakorolt hatását, valamint az antiepileptikumok hatásmechanizmusát és teratogenitását. Orv. Hetil., 2016, 157(15), 563-568.Kulcsszavak: epilepszia, antiepileptikumok, fejlődési rendellenesség, teratogenitás, esélyhányados, relatív kockázat Preconceptional and perinatal challenges of pregnancy in women with epilepsyReproductive-aged women with epilepsy may present a number of specific issues to be managed in daily clinical practice. The impact of epileptic seizures and antiepileptic therapy on pregnancy outcome and the risk of teratogenicity should be minimized, which require careful attention and cooperation between obstetric gynecologyst and neurologist. The aim of the present paper is to review the impact of epilepsy attack on fetus and the pathomechanism and teratogenic effect of antiepileptic drugs.Keywords: epilepsy, antiepileptic treatment, congenital malformations, teratogenity, odds ratio, relative risk Vanya, M., Devosa, I., Szok, D., Bártfai, Gy. [Preconceptional and perinatal challenges of pregnancy in women with epilepsy]. Orv. Hetil., 2016, 157(15), 563-568. Minden, gyermeket vállaló reproduktív korú nő számára elengedhetetlen a fogantatás előtti tanácsadás, valamint az ezt követő adekvát várandósgondozás. Azonban epilepsziabetegséggel küzdők esetén a megfelelő rohammentesség és az antiepileptikus terápia (AED) teratogenitásának minimálisra csökkentése kiemelten fontos, hiszen a következményes congenitalis malformatiók az első trimeszterben lejátszodó organogenesissel interferálnak, ezért ajánlatos, hogy gyermekáldás tervezése előtt minden, gyógyszeres terápiában részesülő asszony felkeresse neurológus kezelőorvosát, és az epilepszia sú-lyosságának szem előtt tartásával a várható kockázat és haszon mérlegelésével esetlegesen új gyógyszeres terápia kerüljön beállításra [1,2].A stabil rohammentesség az optimális cél a lehető legkisebb kockázat mellett. Az anyai és magzati kockázati tényezők egyidejű mérlegelése szükséges, hiszen a gyógyszerek nem megfelelő koncentrációjú plazmaszintje kontrollálatlan tónusos-clonusos görcsrohamokhoz vezethet, amely mind az anya, mind a magzat számára súlyos következményekkel járhat, és potenciálisan veszé-lyesebb lehet, mint maga az AED. Amennyiben lehetsé-ges, kiemelt jelentőségű a politerápiában részesülők monoterápiára átállítása a lehető legalacsonyabb hatásos

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Plasma concentrations of lamotrigine and its 2‐N‐glucuronide metabolite during pregnancy in women with epilepsy

Cited by 96 publications

References 21 publications

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

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

Trends in maternal deaths from epilepsy in the United Kingdom: a 30-year retrospective review

Epilepsziával szövődött terhesség preconceptionalis és perinatalis kihívásai

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