Placental transfer of drugs

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 endometriunX/ 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. 

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 mdrlajb (—j—) 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/ digoxhi/ saquinavir and paclitaxel/ was increased 2.4-/ 7-, and 16-fold/ respectively/ in the knockout mice compared to transport in the wild-type animals. In another murine study/ mdrlajh (—j—) fetuses were susceptible to cleft palate malformation induced by prenatal exposure to a photoisomer of avermectin Bla/ whereas their wild-type litter mates 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/ nelhnavir/ ritonavh/ saquinivir/ and lopinavir/ are known P-gp substrates and do not cross the placenta in detectable levels (98). 

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Pacifici GM, NattoH R (1995) Placental transfer of drugs administered to the mother. Clin Pharmacokinet 28 235-269... 

Nau H Liddiard C (1978) Placental transfer of drugs during early human pregnancy. In Neubert D, Merker H-J, Nau H, Langman J ed. Role of pharmacokinetics in prenatal and perinatal toxicology. Stuttgart, Georg Thieme, pp 465-481. 

In Chapter 2 the significance of the placental transfer of drugs from the maternal circulation into the fetus was discussed. At that time, the prototypic teratogen thalidomide was discussed along with several contemporary drugs such as alcohol and cocaine. By the time that thalidomide was finally removed from the market and the medicine cabinets, it had caused severe deformities in approximately 10,000 children in 46 countries. 

Placental transfer of drug before birth Differing drug action Altered pharmacokinetics Increased percutaneous absorption Decreased renal/hepatic function Decreased plasma protein binding Use of multiple drugs... 

T. Tuntland, A. Odinecs, C.M. Pereira, C. Nosbisch, and J.D. Unadkat. In vitro models to predict the in vivo mechanism, rate, and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol. 180 198-206 (1999). 

Placental transfer of local anesthetics is known to occur rapidly, fetal blood concentrations generally reflecting those found in the mother. However, the quantity of drug crossing to the fetus is also related to the... 

Uematsu, T., Yamada, K., Matsuno, H., and Nakashima, M., The measurement of haloperidol and reduced haloperidol in neonatal hair as an index of placental transfer of maternal haloperidol. Then Drug Monit., 13, 183, 1991. 

GC-MS methods provide greater specificity and in many cases sensitivity when compared with more conventional techniques. They offer increased scope for the study of pharmacokinetics and of plasma concentration in relation to biological effect. SIM assay has been applied to the investigation of placental transfer of lipid soluble drugs and their subsequent elimination in the newborn (barbiturates, diphenylhydantoin, caffeine, pethidine and diazepam [122,408] diphenylhydantoin [411] amylobarbitone and 3 -hydroxyamylobarbitone [83,423]). 

Maternal hypotension and excessive placental transfer of local anesthetics and other drugs, for example narcotics or sedatives, given to the mother before or during delivery are the main causes of neonatal death related to the use of these agents in obstetrics. However, deaths are very infrequent (155). 

Placental transfer of D-tubocurarine occurs (as with aU relaxants) and low concentrations of the drug have been detected in umbilical blood. Under normal circumstances no untoward effects have been reported in neonates. 

Dencker L, Danielsson BR. 1987. Transfer of drugs to the embryo and fetus after placentation. In Nau H, Scott WJ Jr, eds. Pharmacokinetics in Teratogenesis. Vol. I. Interspecies Comparison and Matemal/Embryonic-Fetal Drug Transfer, 55-69. 

Foetal depression during spinal and epidural obstetric anaesthesia occurs secondary to maternal hypotension or as a result of placental transfer of the local anaesthetic agent (8, 10 -, 13 ). In this respect, bupivacaine was found to have a low foeto-maternal drug concentration ratio (16 -). When caudal anaesthesia is used, direct injection of the local anaesthetic drug into the foetus is possible (13, Other causes... 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

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