Effects of gestational age on the disposition of propranolol in pregnant sheep

Maternal and fetal disposition of the beta adrenoceptor blocking drug, propranolol was examined in the pregnant sheep from day 95 to day 140 (term, 145 days) of gestation. Propranolol was administered to the mother (bolus dose, 1.5 mg/kg followed by an infusion of 1.2 mg/kg/hr over 3 hr) to achieve an average steady-state maternal total drug concentration of 600 ng/ml. Total steady-state maternal plasma propranolol concentration was 666 +/- 266 ng/ml, reflecting a 4-fold variation in maternal drug clearance and a 14-fold variation in binding. Neither maternal clearance nor binding showed a significant change with gestational age. Total plasma drug concentrations in the fetus increased significantly with gestational age (r = 0.58, P less than .05), due to a concomitant increase in binding (r = 0.66, P less than .01). Fetal steady-state unbound drug concentrations were 50% of those seen in the mother, indicating that the fetus is capable of irreversible elimination of the drug. This ratio did not change with gestational age, suggesting that the capacity of the fetus to eliminate propranolol does not increase detectably in the latter part of pregnancy. The significant correlation between maternal and fetal unbound drug concentrations indicates that a major determinant of fetal exposure to propranolol is the clearance of the drug by the mother.