The molecular weight of the drug also influences the rate of transfer and the amount of drug transferred across the placenta. Drugs with molecular weights of 250–500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization; those with molecular weights of 500–1000 cross the placenta with more difficulty; and those with molecular weights >1000 cross very poorly. An important clinical application of this property is the choice of heparin as an anticoagulant in pregnant women. Because it is a very large (and polar) molecule, heparin is unable to cross the placenta. Unlike warfarin, which is teratogenic and should be avoided during the first trimester and even beyond (as the brain continues to develop), heparin may be safely given to pregnant women who need anticoagulation. Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal antibodies cross the placenta and may cause fetal morbidity, as in Rh incompatibility. Starting in the second trimester of pregnancy, the placenta develops transporters that allow immunoglobulins to cross from the mother to the fetus despite their large molecular size. This has important clinical implications, because an increasing number of biological drugs (eg, anti-tumor necrosis factor therapy) have been shown to cross the placenta. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fetal dissemination of bacillus Calmette-Guérin (BCG) have been reported. With an increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants.
Because maternal blood has a pH of 7.4, whereas the fetal blood is 7.3, basic drugs with a pKa above 7.4 will be more ionized in the fetal compartment, leading to ion trapping and, hence, to higher fetal levels (see Chapter 1, Ionization of Weak Acids and Weak Bases).
C. Placental Transporters
During the last decade, many drug transporters have been identified in the placenta, with increasing recognition of their effects on drug transfer to the fetus. For example, the P-glycoprotein transporter encoded by the MDR1 gene pumps back into the maternal circulation a variety of drugs, including cancer drugs (eg, vinblastine, doxorubicin) and other agents. Similarly, viral protease inhibitors, which are substrates to P-glycoprotein, achieve only low fetal concentrations—an effect that may increase the risk of vertical HIV infection from the mother to the fetus. The hypoglycemic drug glyburide has lower plasma levels in the fetus as compared with the mother. Recent work has documented that this agent is effluxed from the fetal circulation by the BCRP transporter as well as by the MRP3 transporter located in the placental brush border membrane. In addition, very high maternal protein binding of glyburide (>98.8%) also contributes to lower fetal levels as compared with maternal concentrations.
D. Protein Binding