The placenta was long thought to be a barrier to drugs and chemicals administered to the mother. However, the thalidomide tragedy, reported independently by McBride (75) and Lenz (76), showed that the placenta was capable of transferring drugs ingested by the mother to the fetus, with the potential for great harm. On the other hand, placental transfer of drugs administered to the mother has been used to treat fetal arrhythmias, congestive heart failure, and other conditions (77).
The placenta develops from a portion of the zygote and thus has the same genetic endowment as the developing fetus (78). The embryonic/fetal component consists of trophoblastic-derived chorionic villi, which invade the maternal endometrium and are exposed directly to maternal blood in lake-like structures called lacunae. These villi create the large surface area necessary for maternal-fetal transfer in what becomes the intervillous space of the placenta. Here the maternal blood pressure supplies pulsatile blood flow in jetlike streams from the spiral arteries of the endometrium, to bathe the chorionic villi and allow for transfer of gases, nutrients, and metabolic products. Biologically, the human placenta is classified as a hemochorial placenta because maternal blood is in direct contact with the fetal chorionic membrane. It is this membrane that determines what is transferred to the fetus.
For the most part, drugs and other substances given to the mother will be transferred to the fetus. Drugs cross the placenta largely by simple diffusion.
Factors affecting drug transfer are similar to those affecting transfer across other biological membranes and include the molecular mass, lipid solubility, and degree of ionization of the compound. Generally, drugs and chemicals with a molecular mass of less than 600 Da traverse the placenta readily, while drugs with a molecular mass larger than 1000 Da transfer less readily, if at all. Compounds that are uncharged and more lipid soluble are also more readily transferred.
Recently, P-glycoprotein (P-gp) has been shown to play a critical role in the active transport of a large number of maternally administered drugs back into maternal circulation and away from the fetus. As described in Chapter 14, P-gp is a large, 140-170-kDa transmembrane phospho-glycoprotein whose role as an energy-dependent efflux transporter was first elucidated in the investigation of cellular mul-tidrug resistance. Coded for by the MDR1 gene, P-gp belongs to a superfamily of ATP-binding cassette transporters that are present in all organisms, from bacteria to humans (79-81). Actively excreting absorbed molecules from the cytoplasm, the evolutionary job of P-gp has been to reduce exposure to xeno-biotics, or foreign, natural toxins (82, 83). Numerous seemingly structurally unrelated drugs are substrates for this transporter. In general, these compounds can be categorized as hydrophobic, often planar aromatic molecules that are neutral or positively charged at physiological pH.
In humans, P-gp is expressed on trophoblastic cells throughout pregnancy (82, 84-86). It has been located on apical surfaces of endodermal cells of the mouse yolk sac (87), in the vesicles of the brush border membrane of the human syncytiotrophoblast that directly faces maternal blood, but not within maternal vascular endothelium (83, 84, 86-95). Actively transporting molecules in a basolateral-to-apical direction, the role of P-gp within the placenta is similar to its function at other sites: it extrudes drugs from the placenta back into maternal circulation, thereby protecting the developing fetus from potential toxic factors within the maternal circulation (95).
In genetically altered mdr1a/b (-/-) knockout mice without P-gp, both transplacental transport of P-gp substrates and the incidence of fetal malformations increase (93). Transplacental transport of the P-gp substrates, digoxin, saquinavir and paclitaxel, was increased 2.4-, 7-, and 16-fold, respectively, in the knockout mice compared to transport in the wildtype animals. In another murine study, mdr1a/b (-/-) fetuses were susceptible to cleft palate malformation induced by prenatal exposure to a photoisomer of avermectin B1a, whereas their wild-type littermates were protected from the teratogen (87).
An active transport mechanism has long been suspected to account for the placental barrier that causes maternal and fetal concentrations for many drugs to differ (96, 97). Studies of maternal-fetal transport of medications used during pregnancy in HIV-positive women have shown variable penetration into the fetus (98, 99). Whereas the maternal-fetal drug ratios for zidovudine, lamivudine, and nevirapine (approximately 0.85,1.0, and 0.9, respectively) demonstrate good fetal penetration, most protease inhibitors, nelfinavir, ritonavir, saquinivir, and lopinavir, are known P-gp substrates and do not cross the placenta in detectable levels (98).
Several studies have examined the interaction between selective serotonin reuptake inhibitors (SSRIs) and P-gp and have shown that not all members of this class of drugs are P-gp substrates. Concentrations of paroxetine and venlafaxine, but not fluox-etine, were significantly increased in the brains of mdr1a/b (-/-) knockout mice compared to concentrations in the wild-type mice.(100) In cell culture studies, sertraline, its metabolite desmethylsertraline, and paroxetine were shown to be potent inhibitors of P-gp; however, citalopram and venlafaxine were only weak inhibitors (101, 102).
There are factors that affect the transfer of drugs and chemicals that are unique to the placenta. The placenta has a pore system that allows for bulk water flow across the placenta and can be responsible for small drugs and chemicals crossing the membrane by solvent drag. Within the placenta, there is also a process of endocytosis that is capable of transferring large immunoglobulins to the fetus. Placental tissue has a full complement of cytochrome enzymes capable of metabolizing drugs and chemicals, and some of these metabolites may then transfer more readily to the fetus than the parent drugs do. The permeability and diffusion properties of the placenta may increase as the placenta matures due to a decrease in thickness of the trophoblastic epithelium forming the chorionic membrane.
One of the factors affecting drug transfer to the fetus is the amount of drug delivered to the intervillous space by utero-placental blood flow. Blood flow to the uterus and placenta increases during pregnancy, from 50 mL/min at 10 weeks' gestation to 500-600 mL/min at term (78). Maternal blood flow to the uterus is also influenced by posture, diseases affecting maternal vasculature (such as hypertension and diabetes), placental size, and uterine contractions. For example, maternal cardiac output and utero-placental blood flow are reduced in the supine position and placental perfusion virtually ceases during a contraction. Placentas that are small for gestational age, or those with diffuse calcifications, are less efficient at transferring any maternal compounds to the fetus. Diseases (such as diabetes, which can thicken the chorionic membrane), may also potentially affect diffusion of drugs into the fetal circulation.
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