Diphenhydramine disposition in the sheep maternal-placental-fetal unit: Determinants of plasma drug concentrations in the mother and the fetus

The objective of this study was to identify the important factors that dete rmine plasma concentrations,of diphenhydramine (DPHM) in the mother and the fetus after maternal as well as fetal steady-state drug administration. In ter-relationships were evaluated between maternal and fetal placental and n onplacental clearances, plasma protein binding, and steady-state plasma con centrations of DPHM among data obtained from 18 pregnant sheep during late gestation. The major determinant of plasma DPHM concentrations in the mothe r after maternal as well as fetal administration appears to be maternal pla sma protein binding and maternal nonplacental clearance. In contrast, the m ajor determinant of fetal plasma DPHM concentrations after maternal drug ad ministration was the extent of fetal first-pass hepatic drug uptake from th e umbilical vein. However, after fetal drug administration, the fetal plasm a concentrations were related to the extent of fetal plasma protein binding and fetal placental and nonplacental clearances. The index of fetal-to-mat ernal placental drug transfer after fetal drug administration (steady-state maternal-to-fetal plasma concentration ratio) was related to steady-state fetal plasma unbound fraction and fetal placental and nonplacental clearanc e. However, this index was not related to the magnitude of the factors oper ating on the maternal side of the placenta such as maternal plasma protein binding and maternal nonplacental clearance. This might indicate a lack of complete equilibration of the unbound drug concentrations on the two sides of the placenta at the exchange site.