Drug transporters in the human blood‐placental barrier

Abstract

Studies on the increasing number of transporters found in the placental barrier are gaining momentum, because of their tissue‐specific expression, significance in physiology and disease, and the possible utilization of the emerging knowledge in pharmacology. In the placenta, both syncytiotrophoblast and fetal capillary endothelium express transporters. Fetal exposure is determined by the net effect of combination of transporters, their nature and localization in relation to placental cells and their substrate specificity. Although the significance of placental transporters on human fetal drug exposure is almost an unstudied field so far, their potential use to design drugs that do not cross the placenta is already being pursued. It is thus of interest to review the existing knowledge of human placental transporters. Transporters in all groups which take part in drug transport are found in human placenta. Especially, ATP‐binding cassette transporters ABCG2/breast cancer resistance protein, ABCB1/P‐glycoprotein and ABCC2/MRP2 are all expressed at the apical surface of syncytiotrophoblast facing maternal blood and are putatively important protective proteins both for placental tissue and the fetus, because they are efflux transporters and their substrates include many drugs and also environmental chemicals. Such protective effect has been shown in animals, but these results cannot be directly extrapolated to humans due to interspecies differences in placental structure and function. Experimental models utilizing human placental tissue, especially human placental perfusion, offer valuable possibilities, which have been insufficiently studied so far.

Stickleback embryos use ATP-binding cassette transporters as a buffer against exposure to maternally derived cortisol

“…Indeed, their importance for also regulating exposure to maternal steroids is appreciated in placental mammals [31]. However, this is the first time, to the best of our knowledge, that ABC transporters have been invoked as a mechanism for regulating exposure to maternal steroids in oviparous vertebrates.…”

Effects of Prenatal Cocaine Exposure on Human Pregnancy and Postpartum

“…Many of these transport proteins are found in other organs including; gut, liver, brain and kidney where they perform similar functions. Recognizing the presence and substrate specificity of these transport proteins provides opportunity in drug development to target or exclude drug access to fetal or placental tissues [33,41]. Examples of efflux transporters in the placenta include; ATP binding cassette proteins (ABC), breast cancer resistant proteins (BCRP) and the multiple drug resistance associated proteins (MDRP).…”

“…Perfusion of the isolated human placental cotyledon was described in 1967 by Panigel [68], and in 1970 Nesbitt [69] introduced an apparatus for dual perfusion (both maternal and fetal circuits) which was later modified by other research groups enabling more systematic studies of placental synthetic, metabolic and transport functions [68][69][70][71]. Dual perfusion of the human placenta has been extremely useful in understanding transplacental pharmacokinetics and offers substantial opportunity to enhance drug development during pregnancy [41,57,[72][73][74].…”

Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

“…РОЛЬ ТРАНСПОРТЕРОВ В ЭМБРИОФЕТАЛЬНОМ ВОЗДЕЙСТВИИ ЛЕКАРСТВЕННЫХ СРЕДСТВ С ТЕРАТОГЕННЫМ ПОТЕНЦИАЛОМ В течение последних двух десятков лет описан ряд важ-ных транспортеров ЛС, которым принадлежит ведущая роль в эмбриофетальном воздействии препаратов с тера-тогенным потенциалом [3,106,107]. Синцитиотрофобласт плаценты человека содержит многочисленные транспорт-ные белки, локализованные либо в микроворсинчатой апикальной мембране, обращенной в кровь матери, либо в базальной (плодной) мембране.…”

“…Синцитиотрофобласт плаценты человека содержит многочисленные транспорт-ные белки, локализованные либо в микроворсинчатой апикальной мембране, обращенной в кровь матери, либо в базальной (плодной) мембране. В перемещении лекар-ственных средств через плаценту активно участвуют пять транспортеров -гликопротеин P (P-gp; также известный как MDR1 и ABCB1), семейство трех ассоциированных с множественной лекарственной устойчивостью протеи-нов MRP (MRP1-MRP3) и протеин резистентности рака груди BCRP [106]. Описаны многочисленные полиморфиз-мы этих транспортеров, например для P-gp, MRP2 и BCRP, вовлеченных во взаимодействие с противоэпилептиче-скими препаратами [108].…”