The Developing Liver: the Steady–State Disposition of Propranolol in Pregnant Sheep

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Abstract
The steady–state disposition of the β–adrenoreceptor blocking drug, propranolol, and its metabolite, 4–hydroxypropranolol, was studied in the anesthetized pregnant sheep near term. Following infusion of propranolol to the mother, steady–state plasma concentrations were obtained at three dosage levels in each of the eight animals studied. Blood samples were obtained from: (i) maternal facial artery and hepatic vein; (ii) umbilical vein, and (iii) fetal carotid artery, portal vein, and right hepatic vein. Although total propranolol concentrations in maternal plasma were different from those in umbilical venous plasma, the concentrations of unbound drug were similar, suggesting that unbound drug had equilibrated across the placenta. Approximately 10% of propranolol was unbound in maternal plasma, compared with 30% in fetal plasma. Hepatic extraction of propranolol by the maternal liver was high, so that only 3 to 4% of the drug presented to the liver escaped uptake. In contrast, fetal hepatic extraction was low. Negligible amounts were removed from portal vein blood (right lobe), although one third was extracted from umbilical vein blood (left lobe). Mean peripheral arterial concentrations of 4–hydroxypropranolol were 2– to 3–fold higher in the fetus than in the mother. We conclude that the fetus is exposed to significant concentrations of propranolol and that the fetal hepatic extraction of this drug is considerably less efficient than in the adult. In contrast to the adult liver, the fetal liver does not appear to act as a single homogeneous organ, but rather as two distinct subunits.