Vol. 28, Issue 3, 279-285, March 2000

Diphenhydramine Disposition in the Sheep Maternal-Placental-Fetal Unit: Gestational Age, Plasma Drug Protein Binding, and Umbilical Blood Flow Effects on Clearance

Sanjeev Kumar, George R. Tonn, K. Wayne Riggs, and Dan W. Rurak

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.K., G.R.T., and K.W.R.) and B.C. Research Institute of Children's and Women's Health, Department of Obstetrics and Gynecology, Faculty of Medicine (D.W.R.), The University of British Columbia, Vancouver, British Columbia, Canada

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_um may also contribute to the GA-related fall in CL_fm.