[THE EFFECT OF MAGNESIUM SULPHATE AND LABETALOL ON PLACENTAL VESSELS REACTIVITY USING THE EX-VIVO PLACENTAL PERFUSION MODEL].

BACKGROUND: The use of magnesium sulphate (MgSO4) in combination with antihypertensive drugs such as Labetalol is common in preeclampsia. OBJECTIVES: We aimed to examine the effects of MgSO4 and Labetalol on placental blood vessel reactivity in response to angiotensin II (ATII). METHODS: A dual-perfused single cotyledon model was used. Placentas from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. The intervillous space was infused for 60 minutes with three perfusion protocols: MgSO4 [7 mg%], MgSO4 [7 mg%], with Labetalol [1×10-4 mmol/L] and controls. After 60 minutes, ATII was injected as a bolus into the chorionic artery causing contraction/relaxation response in the fetal compartment. Perfusion pressure was measured continuously during contraction and relaxation phases. RESULTS: Twenty complete experiments were performed (9 controls, 7 with MgSO4 (7mg%) and 4 with MgSO4 [7mg%] and Labetalol [1×10-4 mmol/L]). Basal perfusion pressure did not differ between the treatment groups. Mean area under the pressure curve (AUC), the amplitude of the contraction response and the relaxation factor did not differ significantly between the groups in response to ATII administration. CONCLUSIONS: Magnesium sulphate and Labetalol did not have any effect on feto-placental vasculature reactivity.

Adverse placental effects of valproic acid: Studies in perfused human placentas.

OBJECTIVE: In utero exposure to valproic acid (VPA) has been associated with worse pregnancy outcomes compared to all other antiepileptic drugs. We have previously shown that VPA alters the expression of placental transporters for hormones and nutrients in vitro and in pregnant mice. Here, our aim was to characterize the effects of short exposure to VPA on the expression of carriers for compounds essential for fetal development in human placentas ex vivo, under controlled conditions. METHODS: Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused in the absence or the presence of VPA (42, 83, or 166 µg/mL; n = 6/group) in the maternal perfusate over 180 minutes. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. We additionally measured in the perfused placentas folic acid concentrations and histone acetylation. RESULTS: VPA significantly altered the mRNA levels of major carriers for folic acid, glucose, choline, thyroid hormones, and serotonin (P < .05) and reduced placental folate concentrations by 25%-35% (P = .059). The effects were observed at therapeutic concentrations sufficient to enhance placental histone acetylation, and some were concentration-dependent. SIGNIFICANCE: Our results point to the placenta as a novel target of VPA, implying potential involvement of the placenta in VPA's adverse fetal outcomes.

The Placental Barrier: the Gate and the Fate in Drug Distribution.

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.

Antiepileptic drugs alter the expression of placental carriers: An in vitro study in a human placental cell line.

OBJECTIVE: 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 α, FRα) 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 FRα 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.

Maternal-fetal transfer of indocyanine green across the perfused human placenta.

Indocyanine green (ICG) is an FDA-approved near-infrared imaging probe, given also to pregnant women. We aimed to characterize ICG's transplacental transfer using the ex-vivo perfusion model. Placentas were obtained from caesarean deliveries. Cotyledons were cannulated and dually perfused. ICG, 9.6µg/mL and antipyrine (50µg/mL) were added to the maternal circulation in the absence (n=4) or the presence of the organic anion transporting polypeptide (OATPs) inhibitor rifampin (10µg/mL; n=5) or the P-glycoprotein inhibitor valspodar (2µg/mL; n=3). ICG's maternal-to-fetal transfer was evaluated over 180min. The cumulative percent of ICG in the fetal reservoir was minor. When ICG transfer was normalized to that of antipyrine, it was lower in the presence of rifampin (a 41% decrease; p<0.05). Valspodar did not appear to modify the kinetics of ICG. ICG's transplacental transfer is minimal and is probably OATP-mediated. The placenta is an effective protective barrier to ICG's distribution into the fetus.

Drug Interactions at the Human Placenta: What is the Evidence?

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.