DETERMINANTS OF PLACENTAL DRUG TRANSFER - STUDIES IN THE ISOLATED-PERFUSED HUMAN PLACENTA

There is little information on the effects of maternal and fetal placental blood flow rates, which can change independently, on the placental transfer rate of drugs of different placental permeabilities. We examined the effects of varying maternal and fetal perfusion flow rates on the placental transfer of three model compounds; antipyrine (high permeability), diclofenac (intermediate permeability), and cimetidine (low permeability) in the single-pass, dual-perfused lobule of the isolated human placenta. In variable flow ratio experiments (n = 9) fetal perfusate flow rate was held constant while a different maternal flow rate was used in each of five 25-min phases such that the maternal/fetal flow ratio ranged from 0.16 to 3.3. In constant flow ratio experiments (n = 4), the flow ratio was kept at 2.0, while maternal and fetal flow rates were varied from 4-18 and 2-9 mL/min, respectively. In the variable flow ratio experiments, the fetal transfer fraction (fetal venous/maternal arterial drug concentrations) varied approximately fivefold among the five phases for each of the three drugs. Therefore, placental transfer was flow dependent regardless of placental drug permeability. By contrast, in the constant flow ratio experiments, fetal transfer fraction was unchanged throughout the five phases for each of the three drugs. Of the various kinetic models that have been formulated to account for the different possible vessel geometries, the double pool flow model, which is a venous equilibrium model and predicts the least efficient drug transfer rate of those proposed, together with a small maternal arteriovenous shunt, produced the best fit overall. These findings suggest that simple clearance concepts of flow dependence at high drug permeability and flow independence at low drug permeability may not be adequate to apply to drug transfer in the placenta.