223 Placental Transfer of the Protease Inhibitor Nelfinavir in the Dual in Vitro Placenta Perfusion Model

Intro: The protease inhibitor nelfinavir is a common drug for treatment of HIV in pregnancy. Pairs of serum samples of maternal vein - and umbilical cord blood show very low levels of nelfinavir in umbilical cord blood. These results could be caused by an backward efflux of Nelfinavir into the maternal circulation by p-glycoprotein, which is highly expressed in the placenta. Nelfinavir is a known substrate of p-glycoprotein.Aim: Measurement of placental transfer of nelfinavir and determination of an active transport Material and Methods: Placentas were obtained after written informed consent. Dual closed loop in vitro perfusion of isolated cotyledons (n=12): Perfusion experiments in 4 phases: 1. stabilization and control phase (1h); 2. addition of nelfinavir into first circuit (either maternal or fetal) and measurement of nelfinavir transfer (3h); 3. washout phase (0.5h) followed by; 4. addition of nelfinavir into the second circuit. The order of nelfinavir administration (first maternal or first fetal) was randomized. These transfer data were normalized with the antipyrine permeability to correct for diffusional differences between the experiments. Control parameters for vital placental tissue were glucose consumption, lactate production, leptin production and permeability of creatinine and antipyrine.Results: The permeability ratio of nelfinavir:antipyrine in materno-fetal direction was not significant different from the permeability ratio in fetal-maternal direction (0.5±0.5 v 0.3±0.4). Glucose consumption (0.23±0.07 μmol/g/min), lactate production (0.42±0.12 μmol/g/min) and leptin release (225pg/g/min) indicated a normal metabolism of the tissue. Feto-maternal leakage was below 4ml/h.Conclusion: It is unlikely that active directional transporters are involved in the placental transfer of nelfinavir. The observed low fetal serum concentrations in treated pregnancies are rather caused by other mechanisms like high plasma protein binding or drug metabolism.