Diphenhydramine disposition in the sheep maternal–Placental–Fetal unit: Determinants of plasma drug concentrations in the mother and the fetus

• Published in: Journal of pharmaceutical sciences Vol. 88; no. 12; pp. 1259 - 1265
• Main Authors: Kumar, Sanjeev, Tonn, George R., Riggs, K.Wayne, Rurak, Dan W.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.12.1999; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Animals; Biological and medical sciences; Blood Proteins - metabolism; Diphenhydramine - pharmacokinetics; Female; Fetus - metabolism; Histamine and antagonists. Allergy; Histamine H1 Antagonists - pharmacokinetics; Humans; Maternal-Fetal Exchange; Medical sciences; Models, Biological; Pharmacology. Drug treatments; Placenta - metabolism; Pregnancy; Protein Binding; Sheep; Tissue Distribution; Intravenous administration; Placental transfer; Diphenhydramine; Antihistaminic; Blood; Blood plasma; Pregnancy; Vertebrata; Equilibrium state; Mammalia; Placenta; Animal; Female; Fetus; Sheep; Artiodactyla; Antagonist; Pharmacokinetics; H1 Histamine receptor; Ungulata; Antiemetic
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1021/js990244l

The objective of this study was to identify the important factors that determine plasma concentrations of diphenhydramine (DPHM) in the mother and the fetus after maternal as well as fetal steady-state drug administration. Inter-relationships were evaluated between maternal and fetal placental and nonplacental clearances, plasma protein binding, and steady-state plasma concentrations of DPHM among data obtained from 18 pregnant sheep during late gestation. The major determinant of plasma DPHM concentrations in the mother after maternal as well as fetal administration appears to be maternal plasma protein binding and maternal nonplacental clearance. In contrast, the major determinant of fetal plasma DPHM concentrations after maternal drug administration was the extent of fetal first-pass hepatic drug uptake from the umbilical vein. However, after fetal drug administration, the fetal plasma concentrations were related to the extent of fetal plasma protein binding and fetal placental and nonplacental clearances. The index of fetal-to-maternal 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 clearance. However, this index was not related to the magnitude of the factors operating 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.