The measurement of placental drug clearance in near-term sheep: indomethacin.

A technique has been developed to measure diffusion limited placental clearance. The technique is demonstrated with indomethacin as the test substance. [14C]Indomethacin was injected as a bolus into the fetal hindlimb vein of eight chronically catheterized, near-term ewes and fetuses. Simultaneously, [3H]indomethacin was infused into the ewes. Maternal and fetal blood samples were taken before the injection of radioactivity and at 60-min intervals for 300 min. The blood was assayed for radioactivity. At the end of the experiment, fetal and maternal placental blood flows were measured with the radioactively labeled microsphere technique. The following formula was used to calculate the placental clearance (Cp) of indomethacin: Cp = Ctot X F/M where Ctot is the total clearance of indomethacin from the fetal circulation as measured by the rate of loss of [14C]indomethacin from the fetal circulation and is the sum of the placental clearance and the fetal tissue clearance (Cf), F and M are the fetal and maternal steady-state concentrations of [3H]indomethacin. The placental clearance of indomethacin was 2.10 +/- 0.32 ml/min/kg. The fetal tissue clearance of indomethacin was 3.63 +/- 0.58 ml/min/kg. The degree of diffusion limitation for the placental transfer of indomethacin was 97%.