Abstract

The objective of this study was to examine the interrelationships between maternal and fetal plasma drug protein binding, umbilical blood flow (Q_um), gestational age (GA), and maternal-fetal diphenhydramine (DPHM) clearances in chronically instrumented pregnant sheep. Maternal and fetal DPHM placental (CL_mf and CL_fm, respectively) and nonplacental (CL_mo and CL_fo, respectively) clearances and steady-state plasma protein binding were determined in 18 pregnant sheep at 124 to 140 days' gestation (term, ∼145 days). The data demonstrated a highly significant fall of ∼66% in CL_fm and a decreasing trend in CL_fo (∼47%) over the GA range studied. However, no such relationships existed between GA and CL_mf or CL_mo. Concomitant with this was a decrease in fetal DPHM plasma unbound fraction with GA, with no such change being evident in the mother. Both CL_mo and CL_fo were related to the respective DPHM plasma unbound fraction. A strong relationship also existed between fetal plasma unbound fraction and CL_fm. Thus, the decrease in fetal unbound fraction of DPHM during gestation could contribute to the fall in CL_fm, and possibly CL_fo. However, over the GA range studied, fetal DPHM free fraction decreased by ∼47%, whereas CL_fm fell by ∼66%. Because fetal unbound fraction and CL_fm are linearly related, the GA-associated fall in unbound fraction appears to be insufficient to account for the entire decline in CL_fm. In separate studies in pregnant sheep, we observed a ∼40% fall in weight-normalized Q_um between 125 and 137 days' gestation. Because CL_fm for DPHM is similar to that of flow-limited compounds (e.g., ethanol, antipyrine), this decrease in Q_ummay also contribute to the GA-related fall in CL_fm.