Placental transfer and renal elimination of cimetidine in maternal and fetal sheep.

The placental transfer and renal elimination of cimetidine were studied at steady state in near-term pregnant sheep. In seven nonanesthetized sheep, maternal dosage produced mean steady-state plasma concentrations of 776 +/- 217 ng/ml in the mother and 32 +/- 15 ng/ml in the fetus. Total cimetidine clearance was 41.63 +/- 9.10 liters/hr in the mother, whereas renal cimetidine clearance was 29.96 +/- 15.74 liters/hr in the mother and 1.53 +/- 0.48 liters/hr in the fetus. The mean ratio of cimetidine/creatinine renal clearance was similar in fetus and adult and was considerably greater than unity (7.5 and 7.1, respectively), suggesting active tubular secretion of equal efficiency in both. Fetal dosage in six of the nonanesthetized preparations reversed the maternal-fetal plasma cimetidine concentration gradient (fetal plasma = 16,895 +/- 5,507 ng/ml; maternal plasma = 513 +/- 184 ng/ml). At these very high fetal plasma concentrations, the mean fetal cimetidine/creatinine clearance ratio (2.1) was significantly lower, consistent with the saturation of an active renal tubular secretory process. In four anesthetized sheep, both maternal and fetal renal cimetidine clearances (9.83 +/- 5.39 and 0.32 +/- 0.14 liters/hr, respectively) were 70 to 80% lower than in nonanesthetized sheep. Umbilical venous and arterial cimetidine concentrations were similar (42 +/- 11 and 43 +/- 11 ng/ml, P greater than .05) but substantially less than the maternal plasma concentration (1535 +/- 500 ng/ml). Thus, the principal gradient occurs across the placenta rather than across the fetus. This suggests that, although the fetal kidney can extract cimetidine efficiently, low fetal drug concentrations are primarily due to the placenta and not to fetal drug elimination.