Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function. In this article, we describe key properties of the placental barrier and their modulation by medications. We highlight implications for pharmacotherapy and novel approaches for drug delivery in pregnant women and their fetuses.

SUMMARYObjective: Antiepileptic drugs (AEDs) affect the expression of carriers for drugs and nutrients at several blood-tissue barriers, but their impact on placental carriers is largely unknown. Our aim was to study the effects of AEDs in human placental cells on the expression of carriers for hormones, nutrients, and drugs: folate placental uptake carriers (reduced folate carrier, RFC; folate receptor a, FRa) and efflux transporters (breast cancer resistance protein, BCRP and multidrug resistance protein 2) and thyroid hormone uptake transporters (L-type amino acid transporter-LAT1 and organic anion transporting polypeptides-OATPs). Methods: The human trophoblast BeWo cells were incubated with phenytoin (PHT), valproic acid (VPA), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), or their vehicles at concentrations that mostly represent their therapeutic range. RT-PCR and western blot analysis were utilized to study the effects of AEDs on carriers' mRNA and protein expression, respectively. The activity of BCRP was evaluated by accumulation studies. Results: Compared with controls, VPA-treated cells displayed half the levels of RFC mRNA and protein (p < 0.05) and up to 2.7-fold increases in BCRP mRNA and protein expression (p < 0.05), together with enhanced BCRP activity. PHT increased the expression of BCRP and LAT1 by 2.9-fold and 2.5-fold, respectively (p < 0.01). LTG modulated the levels of FRa transcript and protein, whereas LEV altered those of RFC, LAT1, and OATPs 1A2 and 4A1. CBZ affected carrier expression at the mRNA but not the protein level. All the AEDs altered to a modest extent the transcription of nuclear receptors known to regulate transporter expression. Significance: These findings suggest a possible effect of AEDs on placental transport mechanisms for folate and thyroid hormones as well as those involved in the elimination of potential toxins from the fetus. Identification of AED effects on the placental barrier could be a first step toward a more rational pharmacotherapy and supplemental therapy in pregnant women with epilepsy.

Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes.

Pregnant women (and their fetuses) are treated with a significant number of prescription and non-prescription medications. Interactions among those drugs may affect their efficacy and toxicity in both mother and fetus. Whereas interactions that result in altered drug concentrations in maternal plasma are detectable, those involving modulation of placental transfer mechanisms are rarely reflected by altered drug concentrations in maternal plasma. Therefore, they are often overlooked. Placental-mediated interactions are possible because the placenta is not only a passive diffusional barrier, but also expresses a variety of influx and efflux transporters and drug-metabolizing enzymes. Current data on placental-mediated drug interactions are limited. In rodents, pharmacological or genetic manipulations of placental transporters significantly affect fetal drug exposure. In contrast, studies in human placentae suggest that the magnitude of such interactions is modest in most cases. Nevertheless, under certain circumstances, such interactions may be of clinical significance. This review describes currently known mechanisms of placental-mediated drug interactions and the potential implications of such interactions in humans. Better understanding of those mechanisms is important for minimizing fetal toxicity from drugs while improving their efficacy when directed to treat the fetus.

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