Treatment of epilepsy in pregnant women; importance of placental drug transporters

Epilepsy is a relatively common complication that affects 0.3 – 0.5 % of all pregnant women (Viinikainen et al., 2006). In the USA, up to 1.1 million women with epilepsy are of child-bearing age and give birth to over 20 000 babies each year (Feghali and Mattison, 2011). When uncontrolled during pregnancy, seizures may result in maternal trauma, placental abruption or fetal hypoxia and are potentially life-threatening for both mother and fetus. Many antiepileptic drugs (AEDs) are administered during pregnancy to prevent seizures in mother; however, at the same time the treatment is potentially associated with significantly higher occurrence of fetal abnormalities and developmental disorders especially when used in polytherapy (Tomson and Battino, 2009; Holmes et al., 2011; Vajda et al., 2011; Hernandez-Diaz et al., 2012). Thus, the ultimate aim of epilepsy treatment during pregnancy is a monotherapy leading to seizure-free mother and toxicity-free fetus. Nevertheless, to date, such an antiepileptic agent or treatment regimen has not been found.

Many AEDs are substrates of drug efflux transporters (Loscher and Potschka, 2005) and it is believed that fetal exposure to AEDs may be affected by drug-transporting proteins in the placenta. However, it must be remembered, that the treatment of CNS diseases (including epilepsy) during pregnancy is complicated by the fact, that the compounds must cross the blood-brain barrier (BBB) to fulfill their therapeutic potential. BBB is one of the tightest and most complex of body barriers and, therefore, the compounds are generally small and very lipophilic in nature. It is safe to assume that a compound capable of crossing the blood-brain barrier will easily penetrate the placenta as well. It can hardly be expected that drug efflux transporters will have a significant effect on placental transport of these drugs since their high lipid-solubility and fast passive diffusion surpass the effect of transporter-mediated efflux (as shown in Figure 5). Accordingly, placental perfusion studies have shown that most AEDs (e.g. carbamazepine, oxcarbamazepine, phenytoin, primidone, and lamotrigine), regardless of their affinity to P-glycoprotein, cross the placenta in substantial amounts, and the fetal concentrations are equal or even higher than those in the maternal circulation (Myllynen and Vahakangas, 2002; Myllynen et al., 2005). The only exception here is valproic acid, a low molecular weight fatty acid that is completely ionized at physiological pH. It is obvious that the compound cannot cross biological membranes by passive diffusion, yet it shows potent transplacental transfer (Ishizaki et al., 1981). The mechanism of passage of valproic acid across the placenta has not been explained satisfactorily so far. Using in vitro models of human placental choriocarcinoma cell line (BeWo) and human placental brush-border membrane vesicles it has been proposed that the transplacental passage of valproic acid is mediated by a proton-linked saturable transport system, including the family of monocarboxylic acid transporters (Utoguchi and Audus, 2000; Ushigome et al., 2001; Nakamura et al., 2002).

Lamotrigine is a third generation AED that has been demonstrated by pregnancy registries to be one of the safest medications for treatment in pregnancy due to low occurrence of fetal malformations and uncomplicated cognitive development after birth (Tomson and Battino, 2009; Holmes et al., 2011; Hernandez-Diaz et al., 2012). Therefore, it is considered the drug of first choice for women planning pregnancy (Moore and Aggarwal, 2012). Lamotrigine is rapidly transferred across the perfused human placental cotyledon, reaching similar values in fetal and maternal circulations (Myllynen et al., 2003). When given in monotherapy, the ratio of lamotrigine concentration between newborn and mother ranged from 0.40 to 1.38 (Kacirova et al., 2010) suggesting great interindividual variability, most likely due to variable expression of phase 2 metabolizing enzymes in the placenta and/or genetic polymorphism of glucuronyltransferase UGT2B7 (Collier et al., 2002)(Collier et al., 2002). It is therefore possible, that not only placental transporters but also biotransformation enzymes may affect transplacental passage and fetal drug exposure.

There are several possibilities to limit placental transport of AEDs:

Barzago et al. encapsulated valproic acid into liposomes as drug carriers in an attempt to decrease mother-to-fetus passage of the molecule (Barzago et al., 1996). They confirmed this modification significantly reduced the fetal exposure to valproic acid; however it is feasible to assume that such an alteration will lower also the passage of valproic acid across the BBB and might, therefore, compromise its brain exposure and anticonvulsant activity.

Brain-targeting by intranasal administration offers yet another possibility to ensure safe treatment of epilepsy (and other CNS diseases) in pregnancy. Drugs administered through this route “take a shortcut” from the olfactory region directly to the central nervous system without prior absorption to the systemic circulation. This neuronal connection was found to constitute a direct pathway to the brain, bypassing the BBB (Illum, 2000; Garcia-Garcia et al., 2005) as observed in the case of several CNS active drugs such as carbamazepine (Barakat et al., 2006) or morphine (Westin et al., 2006). In addition, Eskandari et al., (2011) have recently incorporated valproic acid in nanostructured lipid carriers and observed high brain/plasma concentration ratio after intranasal delivery (Eskandari et al., 2011). We, therefore, propose that specific delivery systems for intranasal drug administration will ensure lower plasma concentrations of the drug, thus present reduced risk of materno-fetal transport across the placenta and fetal toxicity.

Finally, considering current knowledge on distribution and substrate specificity of drug transporter it seems logical, that a substrate of an uptake transporter that is oriented in blood-to-brain and fetus-to-mother direction (e.g., some of OATs, OCTs, OATPs) may fulfill the requirement for enhanced delivery of antiepileptic compounds to the brain while keeping mother-to-fetus passage across the placenta to minimum. These transporters thus might represent novel therapeutic targets not only for epilepsy, but other CNS diseases commonly treated in pregnancy, such as depression.