Placental transfer of theophylline during in situ perfusion in the rabbit

Abstract

Many physiological changes take place during pregnancy, and the disposition profile of endogenous and exogenous compounds may change, too. Thus knowledge of the disposition pattern of a compound may be useful in relation to its therapeutic effect(s) and its potential toxicity on the fetus and the newborn. Because the amount of a compound received by the fetus is a product of placental transfer rate, and available maternal amount, and because it is difficult to control and evaluate the factors that may affect such a transfer in women, we set up an in situ perfused placental model in the rabbit. The reliability of the model was borne out by comparing the placental transfer of theophylline with antipyrine, a commonly used marker of placental exchange, at steady state after a two-step infusion at mean arterial plasma concentrations of 8 and 5 $\text{mg}\text{L}$, respectively for theophylline and antipyrine. The rabbit placenta was perfused in situ with a modified Earle's buffer at a 1-$\text{mL}\text{min}$ flow rate. During perfusion, maternal plasma, placental perfusate, biochemical parameters, gas exchange, body temperature, and electrocardiogram were carefully monitored. The maternal plasma and perfusate drug concentrations over time were fitted by appropriate models and kinetic parameters were calculated. Umbilical vein/maternal artery concentration ratios reached equilibrium soon after the loading infusion was stopped for both drugs. Placental clearance averaged 0.62 and 0.77 $\text{mL}\text{min}$ for theophylline and antipyrine, respectively, and the clearance index of theophylline was 0.81 ± 0.07. Although human and rabbit placentas are structurally dissimilar, the rabbit placenta perfused in situ appears to be a useful preparation for measuring the transfer processes and the related and governing factors, of different compounds.