Diphenhydramine disposition in the sheep maternal-placental-fetal unit: gestational age, plasma drug protein binding, and umbilical blood flow effects on clearance.

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, approximately 145 days). The data demonstrated a highly significant fall of approximately 66% in CL(fm) and a decreasing trend in CL(fo) ( approximately 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 approximately 47%, whereas CL(fm) fell by approximately 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 approximately 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(um) may also contribute to the GA-related fall in CL(fm).