Placental transfer of valproic acid after liposome encapsulation during in vitro human placenta perfusion

Valproic acid (VPA) is an antiepileptic drug that crosses the placenta freely. Because its use in pregnancy is associated with an increased incidence of fetal malformation and toxic effects, this study was designed to check whether the placental transfer of VPA entrapped in liposomes was reduced. VPA was encapsulated in dehydrated-rehydrated liposomes prepared with equimolar concentrations of phosphatidylcholine, cholesterol and α- tocopherol. Liposomes were analyzed for their physicochemical characteristics, their stability and percentage of encapsulation of VPA. A system of dual perfusion of an isolated lobule of term human placenta was used. Six placentas were perfused with liposome-VPA and six with free VPA for 180 min using recirculating maternal and fetal circuits. The rate of transfer and time to reach equilibrium of VPA was similar in placentas perfused with free VPA and with liposome-encapsulated VPA. Liposomes significantly reduced VPA transpacental transfer and placental uptake. This was confirmed by FMM at equilibrium, that was 0.548 ± 0.058 in free VPA and 0.393 ± 0.075 in liposome-VPA. The ratio of fetal to maternal concentrations at equilibrium was 0.90 ± 0.10 in controls and 0.66 ± 0.13 in liposome-VPA. The amount of VPA recovered in fetal circulation and in placental tissue were 28 ± 4 and 7 ± 3% in controls and 19 ± 4 and 3 ± 2% in liposome-VPA. In conclusion, our data indicate that encapsulating VPA in liposomes significantly reduces the fetal amount and exposure, and further in vitro and in vivo investigations are needed to optimize the use of liposomes, particularly in pregnancy.