Pharmacokinetics of Flunitrazepam Transfer Across the Rat Term Placenta

Abstract

The aim of the present study was to describe the pharmacokinetics of transplacental passage of flunitrazepam compared with antipyrine as a marker. Placental transfer of both drugs was studied using the rat term placental perfusion system. Flunitrazepam showed considerably rapid passage across the placenta. Both the first-order transfer constant (ktr = 0·171 min−1) and the first-order equilibration constant (keq = 0·061 min−1) tended to be higher than those of antipyrine (ktr = 0·046 min−1, keq = 0·020 min−1). On the other hand, there was a significant difference between flunitrazepam and antipyrine in the foetal concentrations reached at equilibrium (Ceqm = 640·113 and 1541·136 ng mL−1, respectively) and in the foetomaternal concentration ratio at equilibrium (FMCReq = 0·324 and 0·991, respectively). This indicates that flunitrazepam reaches lower concentrations in the foetal compartment and therefore it might be a relatively safe drug when used during pregnancy. Maternal plasma protein binding of both compounds was evaluated by equilibrium dialysis (flunitrazepam = 75·5%, antipyrine = 1·4%). The plasma protein binding could possibly be one of the most important factors in establishing FMCReq.