Influence of maternal plasma protein binding on fetal unbound plasma concentration of propranolol in the pregnant ewe.
According to theory, for a drug of nonrestrictive, flow-limited clearance, a change during pregnancy of the unbound fraction (fu) of drug in maternal plasma should cause a change in steady-state unbound plasma drug concentration (Cu) in maternal plasma, which should also cause a change in fetal Cu. This theory was examined in 14 chronically cannulated, unanesthetized pregnant ewes in which 28 separate experiments were performed during the latter part of gestation. An initial bolus dose and 3-h constant rate infusion of propranolol were administered via the maternal jugular vein and steady-state maternal and fetal carotid arterial plasma total and unbound propranolol concentrations were measured. Fetal Cu (32 +/- 21 ng/mL) was significantly less than maternal Cu (78 +/- 52 ng/mL), due to previously demonstrated fetal hepatic extraction of propranolol. Notwithstanding fetal elimination, there was a significant correlation between fetal Cu and maternal Cu (r = 0.41, p less than 0.025). There was also a strong correlation between fetal Cu and the maternal unbound fraction of drug (fu; r = 0.75, p less than 0.001). We conclude that for propranolol, a drug of nonrestrictive, flow-limited clearance, changes in maternal fu can have a significant influence on fetal Cu, and therefore would be expected to influence the pharmacological effect of the drug in the fetus.
Morgan
D J
DJ
Department of Medicine, University of Melbourne, Austin Hospital, Australia.
Mihaly
G W
GW
Czuba
M A
MA
Ching
M S
MS
Hardy
K J
KJ
Smallwood
R A
RA
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood*; D011433:Propranolol / Q000097:blood*; D011485:Protein Binding; D012756:Sheep
D001798:Blood Proteins; D011433:Propranolol