Transplacental and Nonplacental Clearances of Diphenhydramine in the Chronically Instrumented Pregnant Sheep

Abstract

Pharmacokinetic studies of the histamine H,-receptor antagonist diphenhydramine were conducted in eight chronically Instrumented pregnant sheep at 126-138 days of gestation. Diphenhydramine was administered by simultaneous intravenous bolus Injection and Infusion to steady state given 48h apart, to the ewe and the fetus on separate occasions. Average steady-state drug concentration In plasma after maternal infusion was 212.1 ± 67.8 ng/mL in the mother and 36.3 ± 14.4 ng/mL in the fetus, resulting in a fetal-to-maternal concentration ratio of 0.19 ± 0.10. Following fetal Infusions, maternal and fetal steady-state drug concentrations were 31.1 ± 11.6 and 447.6 ± 185.2 ng/mL, respectively. The free fraction of diphenhydramine determined In the fetus (0.277 ± 0.087) was significantly greater than that in the mother (0.141 ± 0.079). Transplacental and nonplacental clearances were calculated at steady state according to a general two-compartment open model, with drug elimination occurring from both compartments. The total fetal clearance (472.7 ± 215.7 mL/min) was relatively small compared with the total maternal clearance (3426.1 ± 905.8 mL/mln). The transplacental clearance from fetus to mother (264.4 ± 138.7 mL/min) was approximately threefold higher than that from mother to fetus (82.4 ± 40.5 mL/min). Maternal nonplacental clearance (3343.8 ± 890.7 mL/min) accounted for 97.8 ± 1.1% of the maternal total clearance, whereas fetal nonplacental clearance (208.4 ± 80.4 mL/min) accounted for 45.1 ± 4.7% of the fetal total clearance. It is concluded that in the fetus both the transplacental and nonplacental pathways are important for drug elimination.