Mm. Barzago et al., PLACENTAL-TRANSFER OF VALPROIC ACID AFTER LIPOSOME ENCAPSULATION DURING IN-VITRO HUMAN PLACENTA PERFUSION, The Journal of pharmacology and experimental therapeutics, 277(1), 1996, pp. 79-86
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 desi
gned to check whether the placental transfer of VPA entrapped in lipos
omes was reduced. VPA was encapsulated in dehydrated-rehydrated liposo
mes prepared with equimolar concentrations of phosphatidylcholine, cho
lesterol and alpha-tocopherol. Liposomes were analyzed for their physi
cochemical characteristics, their stability and percentage of encapsul
ation of VPA. A system of dual perfusion of an isolated lobule of term
human placenta was used. Six placentas were perfused with liposome-VP
A and six with free VPA for 180 min using recirculating maternal and f
etal circuits. The rate of transfer and time to reach equilibrium of V
PA was similar in placentas perfused with free VPA and with liposome-e
ncapsulated VPA. Liposomes significantly reduced VPA transpacental tra
nsfer 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-V
PA. 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 liposom
es significantly reduces the fetal amount and exposure, and further in
vitro and in vivo investigations are needed to optimize the use of li
posomes, particularly in pregnancy.