Drug disposition in mother and foetus.

1. In pregnancy, plasma protein binding of certain drugs is reduced due to a reduction in serum albumin concentration. Due to an increase in cardiac output in pregnancy there is a 50% increase of effective renal plasma flow, glomerular filtration rate and creatinine clearance. This results in a corresponding increase in renal drug clearance. 2. Placental transfer of small lipophilic molecules from the mother to the foetus is efficient because the placental membrane is a very thin lipophilic membrane, with a large surface area for exchange and high maternal and foetal placental blood flow rates. Nevertheless, placental transfer of relatively hydrophilic molecules is slow and this may limit foetal exposure to the drug where a single maternal dose is concerned. 3. Once a drug has crossed the placenta it passes via the umbilical vein to the foetal liver and then to the systemic circulation of the foetus, which creates a potential foetal hepatic first-pass effect. The activity of most foetal hepatic drug-metabolizing enzymes studied is much less than the adult activity and some enzymes do not appear to be expressed at all. The circulation of the foetal liver is unique because 30-70% of umbilical vein flow is shunted via the ductus venosus. There is also a difference in oxygenation and enzyme content between the left and right lobes of the foetal liver. 4. The foetal kidney is not a very effective route of elimination because renally excreted drug enters the amniotic fluid and recirculates via foetal swallowing. Moreover, foetal renal blood flow is only 3% of cardiac output, compared with 25% in the adult, and renal tubular anion secretion is absent. In conclusion, the extent of foetal exposure of maternally administered drug depends on numerous factors, in particular maternal and foetal elimination mechanisms and placental permeability.