Placenta is a temporary organ that, among many other functions, regulates the exchange of nutrients, waste products and xenobiotics between mother and fetus. Placenta used to be described as a mechanical barrier that only passively protects the fetus against maternal toxins. However, in 1998, Lancas et al., reported P-glycoprotein-mediated efflux of avermectin in the placenta and stressed the role of ATP-binding cassette (ABC) transporters in fetal protection (Lankas et al., 1998). Subsequent disclosure of several other drug transporters in the placental barrier has brought new insights into the question of materno-fetal transport of drugs, fetal protection and detoxication and it has become apparent that efflux and uptake transporters decisively control drug transport across the placenta. To date, the best described of placental drug transporters
are P-glycoprotein and breast cancer resistance protein of the ABC drug efflux transporters family (Ceckova et al., 2006; Hahnova-Cygalova et al., 2011). However, in the recent years, many other transporters have been revealed in the placenta and the topic of transplacental pharmacokinetics is continuously evolving. It is thus obvious that transplacental passage of drugs can no longer be predicted simply on the basis of their physical-chemical properties and binding to plasma proteins; placental drug transporters, their functional expression in the trophoblast and the possibility of drug interactions must be considered to optimize therapy in pregnant women.
Pharmacotherapy during pregnancy is often inevita-ble for medical treatment of the mother, the fetus or both; the number of pregnant women treated with pharmaco-logical drugs has been steadily increasing, partly due to
RevIew ARtIcle
Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure
Frantisek Staud, Lukas Cerveny, and Martina Ceckova
Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove, Czech Republic
AbstractPharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug–drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.Keywords: Gestation, pharmacokinetics, P-glycoprotein, gestational diabetes, HIV, fetal arrhythmias, epilepsy, transplacental, fetal therapy
Address for Correspondence: Frantisek Staud, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic. Tel: +420 495 067 407; Fax: +420 495 067 170. E-mail: [email protected]
(Received 11 June 2012; revised 24 July 2012; accepted 24 July 2012)
advanced diagnostics and partly due to increasing rates of maternity in older women (Thomas & Yates, 2012). In addition, time-lapse between conception and realization of pregnancy may lead to unconscious medication dur-ing pregnancy. A recent systematic review on drug use during pregnancy in developed countries has revealed that 27–93% of pregnant women filled at least one pre-scription excluding vitamins and minerals; the use of medicines with positive evidence of risk ranged from 2.0% in Italy to 59.3% in France and use of drugs contra-indicated in pregnancy ranged from 0.9% in Denmark to 4.6% in the USA (Daw et al., 2011). Several other studies support these findings (Lee et al., 2006; Yang et al., 2008; Irvine et al., 2010). Importantly, many of the compounds that are administered for maternal treatment of acute or chronic disorders may cross the placenta and elicit harmful effects in the developing fetal tissues and organs (Jacqz-Aigrain & Koren, 2005). The transplacental pas-sage of drugs is thus complicating the treatment and, therefore, placental protective function is of an advan-tage. Compromising its role through inhibition of trans-porter proteins or their polymorphisms might lead to unexpected fetal intoxication. To prevent materno-fetal transport of drugs and to decrease fetal drug exposure and fetal toxicity, pharmaceutical research has focused on the development of special technologies and delivery forms such as liposomal encapsulation (Barzago et al., 1996) or drug conjugation with dendrimers (Menjoge et al., 2011), however, with little clinical impact so far.
It should be pointed out, however, that it is not only the mother that is the target of therapy. Over the past several decades, modern technologies of prenatal diagnosis have changed the attitude to fetal diseases from simply termi-nating the pregnancy by interruption to possible active therapy of the fetus. Fetal therapy began almost 60 years ago in the form of peritoneal transfusion for the treatment of fetal anemia (Liley, 1963). About a decade later, transpla-cental therapy was introduced as a non-invasive interven-tion to treat the fetus through administration of the drug to the mother. One of the first examples of transplacental delivery was reported in 1975 by Ampola and colleagues who administered large doses of vitamin B12 to the mother during the last nine weeks of gestation for successful treat-ment of methylmalonic acidemia of the fetus (Ampola et al., 1975). Since then, transplacental medication has been used as a novel approach of modern medicine for the treatment of various fetal disorders; e.g. cardiovascu-lar drugs to treat life-threatening fetal cardiac arrhythmias, antiretrovirals to prevent transmission of HIV from mother to fetus, glucocorticoids to promote fetal lung maturation in cases of threatening premature birth, immunoglobulin and many others (see recent reviews (Hui & Bianchi, 2011; Westgren, 2011)). In the transplacental treatment, the drug is given to the mother and expected to cross the placenta in reasonable time and amount to provide treatment for the fetus. In this scenario, placental transporters might, and in many cases they indeed do, reduce drug availability for the fetus and, therefore, minimize their effectiveness.
For example, P-glycoprotein is blamed for decreasing fetal exposure to maternal digoxin. Inevitably, the transplacen-tal treatment possesses some risks of drug toxicity to the mother raising the challenge of fetus-specific drug delivery systems. In the late 1990s, selective drug targeting during pregnancy was being discussed (Audus, 1999) and several reports by Bajoria and colleagues appeared suggesting specific fetus-targeted delivery forms for drugs that cross the placenta sparingly, such as unilamellar liposomes for thyroxin delivery to the fetus (Bajoria & Contractor, 1997a; Bajoria and Contractor, 1997b; Bajoria et al., 1997a; Bajoria et al., 1997b); however, since then, this line of research has been rather quiet. Pharmacological manipulations, such as modulation of placental drug transporters might offer another option to optimize the transplacental pharmaco-therapy and to maximize fetal drug exposure. For example, inhibition of placental P-glycoprotein may be beneficial in the treatment of HIV positive pregnant women to increase transplacental passage of antiretroviral agents and to reduce the rate of mother-to-child viral transmission. Similarly, for the treatment of fetal tachycardia, pharma-cological inhibition of placental P-glycoprotein would offer the advantage of enhanced digoxin availability to the fetus, while minimizing drug exposure of the mother.
It is evident, that proper understanding of transpla-cental passage of drugs and the role of placental trans-porters in this event will guide the clinicians to more accurate and safer pharmacotherapy during gestation, avoiding or, on the other hand, taking advantage of drug interactions. In addition to clinicians, the discovery of the interactions of drugs with placental transporters is of great interest also to pharmaceutical industry for future drug development to control the degree of fetal exposure (Gedeon & Koren, 2006; Malek & Mattison, 2010). The aim of this review is to summarize current knowledge on the role of drug transporters in the transplacental pharmacokinetics – from mechanistic description to clinical perspectives; we further put this information into the context with several medical conditions that require continuous maternal and/or fetal treatment throughout pregnancy such as fetal arrhythmias, gestational diabetes mellitus, epilepsy, and HIV infection.
Placenta and the models to study placental transport of drugs
To enable reciprocal exchange of nutrients and waste products, the maternal and fetal circulations are brought into close apposition inside the placenta. Maternal blood washes the chorionic villi, in which the fetal blood is cir-culating and nutrients and other substances are brought through the umbilical vein to the developing fetus. In the opposite direction, the fetal vessels branching out from the umbilical arteries bring the waste products from the fetus to the terminal part of the chorionic villi. The surface of chorionic villi is covered by trophoblast that comprises cytotrophoblast stem cells and multinucleated syncy-tiotrophoblast arising from the fusion of differentiated
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cytotrophoblast. In both human and rodents, the placenta is of hemochorial type, which means the trophoblast layer is in direct contact with maternal blood (Enders & Blankenship, 1999; Carter & Enders, 2004). The syncytio-trophoblast layer is polarized with microvillous brush-border membrane facing the maternal blood and basal membrane facing the fetal circulation; the polarized syncytiotrophoblast constitutes the key area for exchange of nutrients, gasses, signal molecules and xenobiotics between mother and her fetus (van der Aa et al., 1998; Sibley, 2009) and is considered the functional part of the placental barrier (Figure 1).
It is generally believed that any chemical substance pres-ent in the maternal circulation can, to at least some extent, cross the placenta. Understandably, for ethical and techni-cal reasons, clinical studies in pregnant women are very rare. Therefore, to evaluate the transport of drugs across the placenta, researchers have to summon the information from a battery of alternative models that mimic the materno-fetal interface. The currently employed approaches include in vitro models of cell cultures, ex vivo perfused human placenta or in situ perfused animal placenta and in vivo transgenic animals (for excellent reviews see (Bode et al., 2006; Vahakangas & Myllynen, 2006; Mitra & Audus, 2008; Vahakangas et al., 2011)). Cell cultures commonly used
as in vitro models for materno-fetal barrier include cell lines derived from malignant or normal placental tissue of human (e.g. BeWo, JEG-3, JAr) or animal (e.g. HRP-1) ori-gin. For evaluating the placental transport functions on in vitro level, trophoblast cells isolated from human or animal placenta can be used for preparation of membrane vesicles (Utoguchi et al., 2000; Gedeon et al., 2008). An important limitation to extrapolating data obtained from these cell lines is the fact that their expression profile of membrane transporters does not necessarily reflect the expression of transporters in the placental tissue (Atkinson et al., 2003; Ceckova et al., 2006; Evseenko et al., 2006; Serrano et al., 2007). Another approach is the cultivation of placental tis-sue explants; however the viability of such slices is usually very limited (Merchant et al., 2004; Gilligan et al., 2012).
Ex vivo perfused human placenta provides the only opportunity to investigate transplacental pharmacokinet-ics directly in the human placenta (Hutson et al., 2011). Alternatively placentas of experimental animals can be perfused in situ, where the connection to the maternal organism is still maintained (Pavek et al., 2003; Staud et al., 2006; Cygalova et al., 2009; Ahmadimoghaddam et al., 2012). The main advantage of these techniques is the possibility to observe transport of substances in both maternal-to-fetal and fetal-to-maternal directions; with the use of specific substrates, inhibitors and concentra-tion-dependent experiments, this approach allows for investigation and quantification of function of transport proteins in the placental barrier.
A valuable in vivo approach is represented by mice lacking the transporter of interest either due to natural deficiency (Lankas et al., 1998; Smit et al., 1999; Jonker et al., 2002) or due to targeted knock-out of the transporter encoding gene(s) (Lagas et al., 2009; Vlaming et al., 2009; DeGorter & Kim, 2011). Mating of transporter-deficient pregnant dams with heterozygous males gives rise to fetuses (and their genetically identical placentas) of three different genotypes; the protective role of the placental transporter can be then evaluated by comparing the rate of drug penetrations to the fetuses across placentas of no, middle and high expression of the transporters (Lagas et al., 2009). To investigate the activity of placental and fetal transporters and their fetoprotective role at different stages of gestation, we introduced a model in which pregnant rats are infused with a substrate and the fetal organs are sub-sequently collected and processed (Cygalova et al., 2008).
Since placenta is a very complex organ, none of the above mentioned models can exactly reflect all the func-tions of the human placental tissue in vivo. It is, therefore, highly advisable to use several alternative approaches to investigate the transplacental pharmacokinetics and func-tions of transporters expressed in the placental trophoblast and then treat the obtained data in a complex manner.
Placental transporters
The functional unit of the placenta, i.e., the polarized cells of trophoblast, expresses a number of transport proteins
Figure 1. Schematic visualization of the placental barrier. CTB, cytotrophoblast; STB, syncytiotrophoblast.
localized either in the apical brush border (maternal-fac-ing) membrane or basolateral (fetal-facing) membrane. Several of these transporters have been described to con-trol the transplacental disposition of many drugs and play a crucial role in fetal protection against maternal toxins. We preferentially focus on transporters, whose expres-sion and function has been confirmed in the placenta.
ABc transporters in the placenta
The ATP-binding cassette (ABC) superfamily comprises 48 members divided into seven subfamilies of membrane proteins that transport a wide variety of substrates (Dean & Annilo, 2005) (Table 1). In terms of drug transport, members of three main subfamilies are of particular
Table 1. ABC transporters in the placenta.Transporter name Encoding gene
(Schinkel et al., 1996; Pavek et al., 2001; Potschka et al., 2001; Potschka and Loscher, 2001a; Potschka et al., 2002; Ceckova-Novotna et al., 2006; Shaik et al., 2007; Storch et al., 2007; Tong et al., 2007; Aleksunes et al., 2008; Nanovskaya et al., 2008; Sudhakaran et al., 2008; Bierman et al., 2010; Hemauer et al., 2010)
BCRP ABCG2 apical H, R, M fetus protection by efflux of substrates from syncytiotrophoblast to mother; survival factor during the formation of the placental syncytium; protects trophoblast against cytokine-induced apoptosis; vectorial transport of sulfate conjugates from fetus to mother (together with OATP2B1)
(Wang et al., 2003; Ceckova et al., 2006; Evseenko et al., 2007a; Evseenko et al., 2007b; Pan et al., 2007; Weiss et al., 2007a; Cygalova et al., 2008; Cygalova et al., 2009; Bierman et al., 2010; Hahnova-Cygalova et al., 2011; Peroni et al., 2011)
MRP1 ABCC1 basolateral H, R, M transport of endogenous substrates (leukotrienes, reduced glutathione) to fetus; vectorial transport of conjugated compounds from mother to fetus (together with OATP4A1)
emtricitabine, abacavir, tenofovir, lamivudine, delavirdine, efavirenz, nevirapine, indinavir, ritonavir, lopinavir, atazanavir, methotrexate and folate analogs, glutathione, glucuronide and sulfate conjugates, heavy metal anionic complexes
(St-Pierre et al., 2000; Potschka and Loscher, 2001b; van der Sandt et al., 2001; Huisman et al., 2002; Atkinson et al., 2003; Leazer and Klaassen, 2003; Potschka et al., 2003a; Potschka et al., 2003b; Leslie et al., 2005; Maher et al., 2005; Ray et al., 2006; Weiss et al., 2007b; Aleksunes et al., 2008; Bousquet et al., 2008; May et al., 2008; Kis et al., 2009; Vahakangas and Myllynen, 2009; Bierman et al., 2010; Keppler, 2011)
MRP2 ABCC2 apical H, R fetus protection by efflux of substrates from syncytiotrophoblast to mother
emtricitabine, abacavir, tenofovir, lamivudine, delavirdine, efavirenz, nevirapine, saquinavir, ritonavir, indinavir, atazanavir, probenecid, cyclosporine, phenytoin, carbamazepine, valproic acid, reduced glutathione, methotrexate and folate analogs, glutathione and glucuronide conjugates, heavy metal anionic complexes, talinolol, pravastatin
Only transporters with recognized physiological/pharmacological role in the placenta are listed in the table. H – human, R – rat, M – mouse. *Not all substrates and inhibitors are listed; we preferentially include those that are clinically relevant in pharmacotherapy during pregnancy.
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importance, i.e. P-glycoprotein (MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRPs, ABCCs). These drug transporters are primarily known for their role in multidrug resistance in cancer, however, they have also been confirmed to play a significant role in the pharma-cokinetics, affecting drug absorption, elimination, and distribution across blood–tissue barriers, including pla-centa (Bodo et al., 2003; Leslie et al., 2005; Fromm & Kim, 2011). In the placenta, ABC transporters actively pump their substrates out of the trophoblast cells into the mater-nal (P-glycoprotein, BCRP, MRP2) or fetal (MRP1) circula-tion (see Figure 2). To date, ABC drug efflux transporters localized to the apical membrane of the trophoblast are considered to be the main active components of the pla-cental barrier as discussed in the following sections.
P-glycoprotein (MDR1, ABcB1)
P-glycoprotein (MDR1/ABCB1) is an ATP-driven drug efflux transporter, which was first observed as a 170 000-dalton surface antigen in hamster ovary cells (Juliano & Ling, 1976). Its presence and activity in the cellular membrane was linked to multidrug resistance in cancer cell lines of various species (Ling & Baker, 1978; Kartner et al., 1983a; Kartner et al., 1983b). Subsequently, P-glycoprotein was identified also in various physiologi-cal, non-tumorous, tissues such as the liver, intestine and kidney, where it affects drug absorption and accelerates elimination of wide range of substrates (Staud et al., 2010). The physiological role of P-glycoprotein seems to consist of protection of sensitive tissues and sanctuaries such as the brain, germ cells and fetus, against potentially
harmful xenobiotics/toxins; functional expression of P-glycoprotein has been demonstrated in the endothe-lial cells of the blood–brain and blood–testis barriers and in the syncytiotrophoblast layer of the placenta; see detailed reviews by (Fromm, 2000; Lin & Yamazaki, 2003; Staud et al., 2010).
In humans, P-glycoprotein is encoded by one gene, ABCB1 (MDR1), while two closely located genes, Abcb1a and Abcb1b (formerly known as mdr1a and mdr1b, respectively), encode the transporter in rodents (Schinkel, 1997; Ambudkar et al., 2003; Kalabis et al., 2005). P-glycoprotein can recognize extremely wide variety of chemically and structurally diverse com-pounds. Its substrates are usually neutral or cationic hydrophobic molecules ranging in size from about 200 Da to over 1000 Da. They comprise anticancer drugs of vinca alkaloids, anthracycline and taxane classes, HIV protease inhibitors, antibiotics, antiepileptics, opioids, antiemetics and many others including also diagnostic dyes like rhodamine 123 or Hoechst 33342 (Ceckova-Novotna et al., 2006; Staud et al., 2010). During the last two decades, intensive effort has been devoted to the identification of inhibitors of P-glycoprotein that could reverse the multidrug resistance in cancer or increase drug absorption from the small intestine; nevertheless this endeavor has not been translated into clinical suc-cess so far (McDevitt & Callaghan, 2007; Tamaki et al., 2011). However, the possibility of drug interactions on P-glycoprotein must be kept in mind when two sub-stances, which are substrates and/or inhibitors of the transporter, are administered together. P-glycoprotein-mediated drug interactions in the small intestine, liver and kidney are considered especially important in drug design and development (Giacomini et al., 2010; Muller & Fromm, 2011). As the human placenta expresses sig-nificant levels of P-glycoprotein, drug interactions on this placental transporter could lead to changes in fetal drug exposure and possible fetal toxicity.
Several studies demonstrated high expression of ABCB1 mRNA in the human placenta and showed the localization of P-glycoprotein in the apical, mother-facing, membrane of placental trophoblast as recently reviewed by Ceckova-Novotna et al. (2006). The placental expression of ABCB1 on the mRNA level was found to be even higher than that in the liver in humans as well as in rats (Bremer et al., 1992; Leazer & Klaassen, 2003) indi-cating its physiological significance. The expression of rat Abcb1a/b genes and their corresponding protein prod-ucts were found in rat placentas from the 11th gestation day up to the term 22nd day of pregnancy although varia-tions in the expression profiles of the particular genes dif-fer among the studies (Trezise et al., 1992; Novotna et al., 2004; Kalabis et al., 2005). In humans, ABCB1 mRNA as well as the encoded protein product were found to be intensively expressed in the trophoblast cells of the first trimester placentas; the expression was found to decrease towards the term (Mylona et al., 1999; Gil et al., 2005; Mathias et al., 2005; Sun et al., 2006).
Figure 2. Schematic depiction of the main ABC drug efflux transporters expressed in the placental barrier and their localization within the trophoblast. BCRP, breast cancer resistance protein; MRP, multidrug resistance-associated protein.
The importance of P-glycoprotein in protecting the fetus from potential toxins was first demonstrated in the study by Lankas et al. (1998) in which a teratogenic P-glycoprotein substrate, avermectine, was shown to cause cleft palate in fetuses deficient in Abcb1a gene (Lankas et al., 1998). Subsequent studies in P-glycoprotein-deficient mice confirmed the role of pla-cental P-glycoprotein in materno-fetal transport of vari-ous substrates, such as digoxin, saquinavir and paclitaxel (Smit et al., 1999; Huisman et al., 2001).
The role of P-glycoprotein in the transplacental phar-macokinetics has also been intensively investigated ex vivo using dually perfused rat and human placenta. Employing various P-glycoprotein substrates and inhibitors, we demonstrated saturable and inhibitable P-glycoprotein-mediated efflux of xenobiotics in the feto-maternal direction (Pavek et al., 2001; Pavek et al., 2003; Cygalova et al., 2009). Based on our data, we concluded that placental P-glycoprotein protects the fetus against xenobiotics from maternal circulation; moreover, it also removes its substrates back to the maternal compartment once they have reached the fetal circulation. The hypoth-esis was further confirmed by studies on dually perfused human placenta, where the transport of P-glycoprotein substrates such as indinavir, saquinavir, paclitaxel, and methadone was significantly higher in the feto-maternal direction when compared with the materno-fetal direction (Molsa et al., 2005; Nanovskaya et al., 2005; Nekhayeva et al., 2005; Sudhakaran et al., 2005; Sudhakaran et al., 2008). The clinical importance of placental P-glycoprotein is further discussed in the “Clinical impact; pharmaco-therapy during pregnancy” section of this review.
Breast cancer resistance protein (BcRP, ABcG2)
Breast cancer resistance protein (BCRP, ABCG2), the latest of ABC drug efflux transporters, was identified in the resis-tant breast cancer derived MCF-7 cell line (Doyle et al., 1998). It was also named “mitoxantrone resistance protein”, MXR (Miyake et al., 1999) or “placental ABC transporter”, ABCP (Allikmets et al., 1998). BCRP can actively efflux a broad range of endogenous and exogenous substrates including anticancer drugs (e.g., doxorubicin, daunoru-bicin, mitoxantrone, topotecan, irinotecan), nucleoside analogues (zidovudine, lamivudine), oral hypoglycemic agent, glyburide, as well as endogenous conjugates (see Table 1). The transporter has been intensively studied for its role in multidrug resistance of many haematological malignancies and solid tumors (Xu et al., 2007; Natarajan et al., 2012). Similarly to P-glycoprotein, BCRP is also widely expressed in absorptive and excretory tissues such as the intestine, kidney and liver where it affects oral availability and hepatobiliar/renal excretion, respectively (Staud & Pavek, 2005). Furthermore, the transporter is functionally expressed in the blood–brain, blood–testis and placental barriers; considerable overlap in tissue distribution and substrate specificity between BCRP and
P-glycoprotein results into cooperation of these two efflux transporters in protection of sensitive tissues such as the CNS or fetus (Cygalova et al., 2009; Agarwal & Elmquist, 2012; Mittapalli et al., 2012).
Since placenta shows the highest BCRP expression of all tissues and even exceeds that of P-glycoprotein (Ceckova et al., 2006), intensive effort has been devoted to describe the physiological and pharmacological roles of BCRP on the materno-fetal interface. Recently two comprehensive papers have thoroughly reviewed the role of BCRP in the placenta and feto-placental unit (Mao, 2008; Hahnova-Cygalova et al., 2011). Similarly to P-glycoprotein, BCRP is localized mainly to the api-cal membrane of syncytiotrophoblast where it pumps its substrates to the maternal circulation. BCRP expres-sion and efflux activity has been confirmed in the com-mon in vitro models of human trophoblast, BeWo and JAr cell lines, in the isolated trophoblast cells (Ceckova et al., 2006; Evseenko et al., 2006) and in the micro-villous membrane vesicles of human term placenta (Kolwankar et al., 2005; Gedeon et al., 2008). In geneti-cally modified mice, Bcrp was shown to limit the fetal exposure to topotecan (Jonker et al., 2000; Jonker et al., 2002), nitrofurantoin (Zhang et al., 2007), phytoestro-gen genistein (Enokizono et al., 2007) and glyburide (Zhou et al., 2008). Using dually perfused rat placenta, we have recently observed Bcrp-mediated transport in the feto-maternal direction and proposed that this transporter not only reduces passage of its substrates from mother to fetus but also removes the drug already present in the fetal circulation, even against concentra-tion gradient (Staud et al., 2006; Cygalova et al., 2009). Similar results were observed in ex vivo perfused human placenta (Myllynen et al., 2008; Pollex et al., 2008). Importantly, the protective role of placental BCRP is further strengthened by expression of the transporter in fetal tissues, such as small intestine, liver or brain (Cygalova et al., 2008).
BCRP seems to be expressed in the placenta through-out the whole period of gestation, however, with varying levels. In rodent placenta, decrease in Bcrp expression toward the term was observed (Kalabis et al., 2005; Yasuda et al., 2005; Wang et al., 2006; Cygalova et al., 2008). In the human placenta, the available data is rather inconsistent; while higher expression of BCRP at mRNA and protein levels was observed in preterm compared to term placentas (Meyer zu Schwabedissen et al., 2006), other studies reported unchanged or slightly increased BCRP expression in the term placentas (Mathias et al., 2005; Yeboah et al., 2006).
Beside its protective role, other physiological functions of BCRP in the placenta have been proposed. Using the model of BeWo cells, Evseenko and colleagues suggested that BCRP most probably serves as a survival factor during the formation of the placental syncytium (Evseenko et al., 2007b). In their subsequent study, these authors further proposed that BCRP transporter also protects tropho-blasts against cytokine-induced apoptosis and possibly
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other extrinsic activators via modulation of ceramide sig-naling (Evseenko et al., 2007a). Together with MRPs and OATP2B1, BCRP also seems to play a role in the transport of steroid sulfates in human placenta (Grube et al., 2007; Mitra & Audus, 2010) (see Figures 2 and 4).
The family of MRP (ABCC) transporters consists of nine membrane proteins that are considered as important efflux pumps for anionic conjugates in mammalian cells. The first transporter of the MRP family, MRP1, was cloned two decades ago by Cole and colleagues (Cole et al., 1992) and shortly afterwards described as an ATP-dependent efflux transporter for anionic conjugates (Jedlitschky et al., 1994; Leier et al., 1994). Although MRPs are vari-able in size and structure, their substrate specificity over-laps significantly. In general, these proteins transport conjugated and unconjugated organic anions (such as leukotriene LTC4) and phase II metabolic products (such as glucuronide-, glutathione- or sulphate- conjugates) (Keppler, 2011). In addition, MRPs can efflux various xenobiotics from cells and influence their pharmacoki-netics (see Table 1) (Szakacs et al., 2006).
Placenta expresses MRP transporters both in the api-cal and basal membranes of the syncytiotrophoblast (see Figure 2) as well as in the endothelium of fetal capillar-ies. However, whereas the importance of P-glycoprotein and BCRP on placental transport of drugs has been well documented, much less is known about the pharmaco-logical/physiological role of placental MRPs.
MRP1 (ABCC1) is expressed in the basolateral mem-brane of trophoblast (Atkinson et al., 2003; Nagashige et al., 2003; Nishikawa et al., 2010) and also in fetal endo-thelia (Nagashige et al., 2003). Significant expression of MRP1/Mrp1 was observed in human as well as in rat and mouse placenta. In all species, the placental expression of MRP1/Mrp1 was found to exceed those in the main excretory organs, liver and kidney, suggesting the impor-tance of this transporter in the placental tissue (Leazer & Klaassen, 2003; Maher et al., 2005; Serrano et al., 2007). The expression pattern of MRP1 during gestation, how-ever, differs among species. Significantly higher MRP1 expression was found in human term placentas, when compared to first trimester placental samples (Pascolo et al., 2003), while no changes in the placental expres-sion of Mrp1 during pregnancy were observed in mice (Aleksunes et al., 2008). Functional expression of MRP1 has also been demonstrated in choriocarcinoma BeWo, JEG and JAr cell lines (Pascolo et al., 2001; Atkinson et al., 2003; Evseenko et al., 2006) and trophoblasts of human term placenta (Serrano et al., 2007). It seems that the primary role of MRP1 in the placenta is to transport endogenous substrates such as leukotrienes rather than xenobiotics. However, if xenobiotics reach the fetal cir-culation, MRP1 is assumed to concentrate them in this compartment (Atkinson et al., 2003). In a recent study,
Nishikawa et al. (2010) hypothesized vectorial transport of conjugated bisphenol A from mother to fetus medi-ated by Oatp4a1 on the apical and Mrp1 on the basolat-eral membrane with subsequent deconjugation in the fetus (Nishikawa et al., 2010). The authors thus provide a potential mechanism to explain long-term adverse effects in animals whose mothers were exposed to bisphenol A during pregnancy.
MRP2 (ABCC2) transporter was originally detected in a cisplatin-resistant human cancer cell line (Taniguchi et al., 1996); apart from anticancer compounds it transports var-ious drugs and heavy metals. Although substrate specifici-ties of MRP1 and MRP2 are very similar, their localization in human placenta is different (Table 1). MRP2 is local-ized, similarly to P-glycoprotein and BCRP, to the apical membrane of the trophoblast (St-Pierre et al., 2000; Meyer zu Schwabedissen et al., 2005b) and is, therefore, assumed to protect the fetus against maternal toxins. Indeed, in the perfused human placenta, MRP2 was found to limit materno-fetal transfer of talinolol (May et al., 2008).
Placental expression of many other MRP transport-ers, namely MRP3 (ABCC3), MRP5 (ABCC5), MRP8 (ABCC11) in human and Mrp4 (Abcc4), Mrp5 (Abcc5), Mrp6 (Abcc6), Mrp7 (Abcc10) in rodents was observed (St-Pierre et al., 2000; Bera et al., 2001; Leazer & Klaassen, 2003; Maher et al., 2005; Meyer Zu Schwabedissen et al., 2005a; Serrano et al., 2007; Aleksunes et al., 2008); how-ever, further experiments are necessary to evaluate their role in transplacental pharmacokinetics.
Slc transporters in the placenta
While the expression, localization and function of ABC drug efflux transporters in the placenta have been relatively well described using a variety of experimental approaches in several mammal species, much less atten-tion has been paid to the role of the solute carrier (SLC) family of transporters in the placenta. This transporter superfamily is by far the largest family of transporters, consisting of over 300 members that have been described in many tissues throughout the body. Some of the mem-bers are relatively substrate-specific, mediating transport of endogenous compounds such as sugars, amino acids or nucleosides; some other members, on the contrary, show wide substrate specificity, recognizing broad spectrum of molecular structures and dimensions (see Table 2). These are called “polyspecific” transporters and play a major role in drug elimination, especially in excretory organs, typically kidney and liver (Koepsell & Endou, 2004).
In general, SLC transporters in the placenta mostly facilitate energy-independent uptake of hydrophilic or charged molecules by the trophoblast cells. Once in the trophoblast, these substrates might be either utilized for placenta´s own need (such as de novo synthesis of placental hormones) or pumped out of the cell by another, SLC or ABC transporter (see Figures 3 and 4). In the following section, we focus on those transporters that have been identified in the placenta, i.e. organic
cation transporters, organic anion transporters, carni-tine transporters, nucleoside transporters, organic anion transporting polypeptides and the recently discovered multidrug and toxin extrusion proteins (MATE).
Organic cation transporters (Octs)
Organic cation transporters (OCTs) are polyspecific transport proteins of the SLC22A family transporting mainly small monovalent organic cations with rela-tive molecular mass below 500. The first member of the organic cation transporter family, Oct1, was cloned from a rat kidney cDNA library in 1994 (Grundemann et al., 1994). Shortly after, organic cation transporters with high homology to OCT1, i.e. OCT2 and OCT3, and many orthologs from different species were cloned and charac-terized (Okuda et al., 1996; Gorboulev et al., 1997; Zhang et al., 1997a; Zhang et al., 1997b; Terashita et al., 1998; Urakami et al., 1998; Karbach et al., 2000).
OCTs are uniporters that enable cellular uptake of their substrates by facilitated diffusion. Transport of organic cations mediated by OCT1, OCT2 or OCT3 is electrogenic, independent of Na+, and reversible with respect to direction (Koepsell & Endou, 2004). The driv-ing force is supplied by the electrochemical gradient of the transported organic cation. Substrates of OCT trans-porters are usually hydrophilic organic cations of widely diverse chemical structures that are positively charged at
physiological pH. To date, tens of compounds, including endogenous molecules, clinically relevant drugs or tox-ins, have been described as OCT substrates or inhibitors with considerable overlap between OCT isoforms; for exhaustive review see Nies et al. (2011).
Although their physiological importance has not been elucidated in detail, OCTs are known to affect a variety of physiological functions and pathophysiological pro-cesses. Since OCTs are expressed in the intestine, liver, kidney, and biological barriers they control body disposi-tion of endogenous substrates as well as absorption, dis-tribution and excretion of many drugs. Several transgenic and knockout mouse models have been developed to investigate the role of SLC transporters in physiology and pharmacology (DeGorter & Kim, 2011). For functional studies of OCTs, knockout mice deficient in Oct1, Oct2, Oct3 or double knockout (Oct1 and Oct2) were generated (Jonker et al., 2001; Zwart et al., 2001; Jonker et al., 2003). All strains were viable, healthy and fertile and displayed no obvious physiological defects, indicating that Octs are not essential for normal physiological functioning in mice. Regarding pharmacokinetic behavior, genetic ablation of Oct1 in mice demonstrated the importance of this isoform in hepatic elimination (Jonker et al., 2001) while studies with Oct3-knockout mice revealed
Figure 3. Schematic depiction of the main SLC drug transporters expressed in the placental barrier and their localization within the trophoblast. CNT1, concentrative nucleoside transporter 1; ENTs, equilibrative nucleoside transporters; MATE1, multidrug and toxin extrusion protein 1; OAT4, organic anion transporter 4; OATP2B1, organic anion-transporting polypeptide 2B1; OATP4A1, organic anion-transporting polypeptide 4A1; OCT3, organic cation transporter 3; OCTN2, carnitine transporter 2.
Figure 4. Schematic depiction of vectorial transport across the placenta mediated by ABC and/or SLC transporters. BCRP, breast cancer resistance protein; BSA, – bisphenol A; CNT1, concentrative nucleoside transporter 1; ENTs, equilibrative nucleoside transporters; MATE1, multidrug and toxin extrusion protein 1; MRP1, multidrug resistance-associated protein 1; OATP2B1, organic anion-transporting polypeptide 2B1; OATP4A1, organic anion-transporting polypeptide 4A1; OCT3, organic cation transporter 3.
the importance of this isoform in the placental transport of organic cations (Zwart et al., 2001). In a recent study, Higgins et al. (2012) reported that ablation of both Oct1 and Oct2 significantly affected metformin pharmacoki-netics in mice but, surprisingly, had no effect on tissue drug exposure and pharmacodynamics, thus challenging the presumption that systemic OCT inhibition will affect metformin pharmacology (Higgins et al., 2012). Further studies will be required to elucidate this issue.
To understand the role of OCTs in drug disposition, it must be remembered that a concerted activity of OCT-mediated uptake with an efflux transport systems is nec-essary for vectorial transport of organic cations across the cells. It is generally believed that OCTs mediate the first step of organic cation transport across biological mem-branes, i.e. the influx from the basolateral side into the cells. The second step, i.e. the efflux from the cell across the apical membrane is mediated by a different trans-porter such as the P-glycoprotein and/or an H+-organic cation antiporter (e.g. OCTN and MATE) (see Figure 4). This concept has been confirmed in the polarized cells of the main excretory organs, kidney and liver, and seems to play an important role in body detoxication (Koepsell et al., 2003; Wright & Dantzler, 2004; Koepsell et al., 2007). We have recently described Oct3-Mate1 vectorial trans-port in the rat placenta (Ahmadimoghaddam et al., 2012).
Despite being similar in structure and function, the tissue distribution of the OCTs differs greatly. OCT1 is expressed mainly in the sinusoidal (i.e. basolateral) membrane of hepatocytes where it mediates the first step in hepatic excretion of cationic drugs (Jonker et al., 2001); it is therefore called “liver-specific” OCT. Its expression in other organs was also confirmed, although in lower lev-els (Gorboulev et al., 1997; Zhang et al., 1997a). Wessler et al. (2001) described functional expression of OCT1 in human placenta concluding the transporter, along with OCT3, is involved in the release of acetylcholine (Wessler et al., 2001). OCT2 is expressed predominantly in the basolateral membrane of renal tubules and is respon-sible for organic cation renal excretion (Grundemann et al., 1994; Gorboulev et al., 1997; Zhang et al., 1997b; Urakami et al., 1998; Jonker et al., 2003); it is, therefore, called “kidney-specific” OCT. Low levels of OCT2 expres-sion in the placenta have also been detected (Urakami et al., 2002). Recently, Saito et al. (2011) reported on large interindividuality in OCT2 levels in human placenta encouraging further investigation of this transporter in placenta. In the rat placenta, Oct2 could not be detected (Wessler et al., 2001; Ahmadimoghaddam et al., 2012). The tissue distribution of OCT3, on the other hand, is much broader than that of OCT1 or OCT2; high levels of OCT3 expression were described in many organs including the reproductive system such as the placenta and uterus (Kekuda et al., 1998; Verhaagh et al., 1999). Current knowledge indicates that of all OCTs, OCT3 is the most abundantly expressed in the placenta of many spe-cies and, therefore, this transporter is covered in more detail in the following section.
OCT3, also known as the extraneuronal monoamine transporter is encoded by SLC22A3 gene. In all species tested, the transporter shows very high expression in the placenta and rather low in kidney and liver (Kekuda et al., 1998; Verhaagh et al., 1999; Wu et al., 2000b; Sata et al., 2005; Alnouti et al., 2006; Ahmadimoghaddam et al., 2012) suggesting OCT3 to be a “placenta-specific” OCT. The transporter has been localized to the baso-lateral, fetus-facing, membrane of the trophoblast in human (Sata et al., 2005) and rat (Ahmadimoghaddam et al., 2012) placenta. To investigate the expression and function of this transporter in the materno-fetal inter-face, several researchers have employed various in vitro, in situ and in vivo models, including JAr human placen-tal choriocarcinoma cell line (Martel & Keating, 2003), human placental basal membrane vesicles (Sata et al., 2005), in situ perfused human (Tertti et al., 2010) or rat (Ahmadimoghaddam et al., 2012) placenta and Oct3 knockout mice (Zwart et al., 2001). However, the out-comes of this intensive research are still confusing and often contradictory. In their original work, Kekuda et al. (1998) logically suggested that OCT3 may be responsible for placental uptake of cationic xenobiotics from the fetal circulation and “may hence be a key player in the barrier function of the placenta to protect the developing fetus from possible deleterious effects of xenobiotics that may be present in the maternal circulation” which has recently been confirmed in rat (Ahmadimoghaddam et al., 2012). Surprising data was gained from Oct3 knockout mice by Zwart et al. (2001) who demonstrated that after admin-istration of MPP+ into the maternal circulation, its con-centrations in the fetus were significantly lower in Oct3 knockout mice when compared to wild-type mice (Zwart et al., 2001). Placental OCT3 was subsequently suggested to constitute a significant leak pathway for xenobiot-ics into the fetus (Ganapathy & Prasad, 2005; Lee et al., 2009). Considering the fact, that Oct3 is an influx trans-porter localized to the fetal-facing membrane one would expect placental Oct3 to have opposite function, i.e. fetal protection, as suggested by Kekuda et al. (1998) in their pioneering article. We assume that interspecies differ-ences might have an important say in this issue since expression of SLC transporters varies widely among mammals. As stated above, vectorial transport of organic cations through excretory organs is typically mediated by synchronized activity of OCTs and MATEs (Ciarimboli, 2008; Giacomini et al., 2010; Ahmadimoghaddam et al., 2012; Yonezawa & Inui, 2012). Since the expression of Mate1 and Mate2 in the murine placenta is rather neg-ligible (Aleksunes et al., 2008; Lickteig et al., 2008) dif-ferent proteins must regulate the transplacental passage of organic cations in mice; therefore, mouse is not an appropriate model to prove the concept of Oct–Mate col-laboration in cation transport across the placenta.
The physiological importance of placental OCT3 has still not been satisfactorily elucidated to date; however, it has been suggested to play a role in the clearance of catecholamines from the fetal circulation (Ganapathy &
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Prasad, 2005). In addition, OCT3, together with OCT1, may also mediate the cellular release of acetylcholine from the placenta during non-neuronal cholinergic regu-lation (Wessler et al., 2001).
Variation in drug transporter expression throughout pregnancy is an important issue. Verhaagh et al. (1999) studied intraindividual variability of OCT3/Oct3 expres-sion in the human and mouse placenta, concluding that the levels of expression decline towards the end of gesta-tion (Verhaagh et al., 1999). On the other hand, in the rat placenta, we have observed increasing expression of Oct3 towards the end of gestation on both mRNA and pro-tein levels (Ahmadimoghaddam & Staud, unpublished data). These interspecies differences must be taken into account when extrapolating experimental data between mammal species.
Organic cation/carnitine transporters (OctNs)
Similarly to OCT transporters, OCTNs are also members of the SLC22A family. Three different transporters have been described, OCTN1 (SLC22A4), OCTN2 (SLC22A5) and OCTN3 SLC22A21 (Koepsell et al., 2007). These transport proteins are expressed in many tissues, includ-ing the placenta, where they mediate the influx of carni-tine as well as cationic molecules.
OCTN1 was first cloned from human fetal liver cDNA in 1997 and other orthologues were subsequently added (Tamai et al., 1997; Tamai et al., 2000; Wu et al., 2000a). It is expressed in many tissues including kidney, skel-etal muscle (Tamai et al., 1997) as well as placenta (Wu et al., 2000a). OCTN1 belongs to the same gene fam-ily and shares structural similarity with OCT3 (Tamai et al., 1997), however, significant differences in transport mechanisms exist between OCTN1 and OCTs (Koepsell & Endou, 2004). Tamai et al. (2007) reported that OCTN1 may serve as an H+/organic cation antiporter, because it can mediate the pH-dependent transport of TEA; this assumption was, however, later questioned by Terada and Inui (2008). In the placenta, OCTN1 is supposed to be localized to the brush border membrane of the syncytiotrophoblast and to mediate the organic cation/H+ antiport process (Ganapathy & Prasad, 2005), how-ever, functional analysis data is needed to confirm this hypothesis. In addition to carnitine, OCTN1 transports many substrates of exogenous origin, such as pyril-amine, quinine, quinidine, and verapamil (Klaassen & Aleksunes, 2010).
OCTN2 is structurally very similar to OCTN1 (Wu et al., 1998) and it functions as an Na+-coupled trans-porter for carnitine (Tamai et al., 1998). Human OCTN2 is mostly expressed in the kidney, placenta, and intes-tine, preferentially in the brush border membrane (Tamai et al., 1998; Lahjouji et al., 2004). In the placenta, OCTN2 is localized to the apical membrane facing the maternal circulation (Lahjouji et al., 2004; Grube et al., 2005). The transporter recognizes a variety of cationic
drugs, such as cephaloridine, quinidine, spironolactone, valproic acid or verapamil and may affect their trans-placental pharmacokinetics (Klaassen & Aleksunes, 2010). Interestingly, while transport of carnitine is Na+-dependent, OCTN2 transports organic cations without involvement of Na+ (Wu et al., 1999). OCTN2 is also expressed in BeWo cell line suggesting these cells as an in vitro placental model to study placental expression, function and regulation of OCTN2 (Rytting & Audus, 2007; Hirano et al., 2008; Rytting & Audus, 2008; Huang et al., 2009).
Relatively little is known about the latest of OCTN transporters, OCTN3. Its expression on mRNA and pro-tein levels was detected in murine testes and epididymal spermatozoa (Kobayashi et al., 2007) and in rat entero-cytes (Duran et al., 2005). OCTN3 has limited affinity for organic cations such as tetraethylammonium and seems to function only as a carnitine transporter (Tamai et al., 2000).
The physiological function of carnitine transporters in the placenta is still not fully understood. However, since carnitine is a cofactor for the transport of long-chain fatty acids into mitochondria for subsequent beta oxidation (Rinaldo et al., 2002) it is presumed that OCTNs trans-port carnitine from mother to fetus to prepare the fetus for a postnatal milk diet (Klaassen & Aleksunes, 2010). Yet another hypothesis was suggested by Shekhawat and colleagues who identified several fatty acid oxida-tion enzymes in the human placenta and speculated that human placental fatty acid oxidation is critical for normal growth and maturation of the placenta and for fueling the energy-consuming functions of the transpla-cental transport (Shekhawat et al., 2003). Subsequently, they used the model of OCTN2 null mice to suggest that the placental OCTNs may have two functions: to trans-fer carnitine from the mother to the fetus and to provide carnitine to the placenta for its own metabolic needs (Shekhawat et al., 2004).
Organic anion transporters (OAts)
Together with OCTs and OCTNs, organic anion trans-porters (OATs) are also members of the SLC22A carrier family. This subfamily consists of several members and most of them operate as anion exchangers, i.e., they couple the uptake of an organic anion into the cell to the release of another organic anion from the cell (Rizwan & Burckhardt, 2007). OATs are characterized by broad sub-strate specificity ranging from small, amphiphilic organic anions of diverse chemical structures to uncharged mol-ecules, and even some organic cations. Substrates of OATs have a molecular weight of up to 500 Da and include clinically used anionic drugs such as antibiotics, antivi-rals, ACE inhibitors, diuretics or NSAIDs (Burckhardt & Burckhardt, 2003). Seven OATs (OAT1–7) have been char-acterized to date, and their expressions were identified in the excretory organs – predominantly in the basolateral (OAT1 and OAT3) and the apical (OAT4) membrane
of the kidney proximal tubule cells and the basolateral membrane of hepatocytes (OAT2).
OAT4 (SLC22A11) transporter is the only organic anion transporter specific to human; abundant expres-sion of OAT4 mRNA was detected in the kidney and placenta (Cha et al., 2000). While in the kidney OAT4 is expressed in the apical membrane of renal proximal tubules (Ekaratanawong et al., 2004), in the human term placenta this transporter is preferentially localized to the basolateral membrane of syncytiotrophoblasts in terminal and intermediate villi (Ugele et al., 2003). OAT4 was found to transport sulfoconjugated estrogens as well as C19-steroids precursors for placental de novo synthesis of estrogens in a sodium-dependent manner (Ugele et al., 2008) and co-localization and interaction with caveolin-1 in primary cultured human placental trophoblast was observed (Lee et al., 2008). In addition, it is believed to mediate the excretion of potentially toxic anionic compounds from the fetus towards the mother.
Organic anion transporting polypeptides (OAtPs)
Organic anion transporting polypeptides are members of the OATP/SLCO family and are mainly involved in the Na+-independent uptake of bile acids in hepatocytes. Their expression in the liver, kidney, blood–brain barrier, small intestine, placenta, and testis suggests that OATPs play an important role in drug distribution and excre-tion; however, their physiological role(s) remain(s) to be elucidated.
Some of these transporters are also expressed in the placenta, especially OATP2B1 (SLCO2B1) also known as OATP-B (St-Pierre et al., 2004). Similar to OAT4, OATP2B1 is also localized to the basal membrane of the syncytio-trophoblast, indicating that both transporter polypep-tides are involved in the placental uptake of fetal derived steroid sulfates (Ugele et al., 2003). In their subsequent study, Ugele et al. (2008) described functional differences between OAT4 and OATP2B1 concluding that OATP2B1 may not be involved in de novo synthesis of placental estrogens but may contribute to the clearance of estrogen sulfates from placental circulation (Ugele et al., 2008). Grube et al. (2007) indicated the potential for a functional interaction between basolateral OATP2B1 and apical BCRP in the transepithelial transport of steroid sulfates in human placenta (Grube et al., 2007) (Figure 4).
In addition to sulfate conjugates, OATP2B1 trans-ports fexofenadine, pravastatine (Nozawa et al., 2004) or glyburide (Satoh et al., 2005) and might thus affect the transplacental passage of these compounds. In their recent study, Tertti et al. (2011) used the model of dually perfused human placenta to investigate the placental transport of repaglinide, an oral hypoglycaemic agent. The authors conclude that the transplacental pharma-cokinetics of this compound may be affected by placen-tal OATP transporters and their polymorphisms (Tertti et al., 2011).
OATP4A1 (SLCO4A1), also known as OATP-E, is pre-dominantly expressed in the apical membrane of the syncytiotrophoblasts, suggesting a functional role for the transplacental transfer of thyroid hormones and other endogenous substrates (Sato et al., 2003). In addition, Nishikawa et al. (2010) have recently suggested vectorial transport of conjugated bisphenol A across the rat pla-centa in which the compound is taken up by trophoblast by Oatp4a1 and then transferred into the fetus by Mrp1 (Nishikawa et al., 2010).
Multidrug and toxin extrusion proteins (MAte)
The family of multidrug and toxin extrusion proteins (MATE, SLC47A) is the most recently categorized one among multidrug transporter families. Although MATE proteins belong to the SLC family, they function as efflux transporters. MATEs are secondary transport systems utilizing an oppositely directed H+ gradient as a driving force for transport of organic cations across cell mem-branes (Tsuda et al., 2007; Terada & Inui, 2008). They were originally identified in Vibrio parahaemolyticus and Escherichia coli, and named NorM and YdhE, respectively (Morita et al., 1998). The first human orthologue was identified by Otsuka et al., 2005 (Otsuka et al., 2005) and named MATE. Other isoforms in human and other mam-mal species have been localized in several tissues, such as kidney, liver, placenta, intestine, testes, skeletal muscle, and heart (Otsuka et al., 2005; Masuda et al., 2006; Hiasa et al., 2007; Lickteig et al., 2008; Ahmadimoghaddam et al., 2012).
MATEs have been known to play an important role in intrinsic and acquired resistance in many bacteria (Kaatz et al., 2005). Recently, their role in the pharmacokinetics and pharmacodynamics has been described (Yonezawa & Inui, 2012). Physiological and pharmacological signifi-cance of Mate1 was investigated in knockout mice model; the animals were viable, fertile with no histopathological differences. However, renal functions were changed indi-cating mild nephropathy (Tsuda et al., 2009). The authors further described affected metformin pharmacokinetics in Mate1(-/-) mice, with markedly increased plasma and renal concentrations and decreased urinary excretion (Tsuda et al., 2009).
Significant differences in the tissue distributions between human MATE2-K and rodent Mate2 were observed, which may be partly due to their classification in class II and III subgroups, respectively (Hiasa et al., 2007). Human MATE2-K counterparts have not been identified in rodents and vice versa rodent MATE2 coun-terparts have not been found in human (Omote et al., 2006; Terada & Inui, 2008). Based on the phylogenetic tree of mammalian MATE transporters, rodent MATE2 is classified into MATE3 family, but not MATE2 family (Hiasa et al., 2007). To avoid further misunderstanding, it was suggested to rename mouse and rat Mate2 as Mate3 (Yonezawa & Inui, 2012).
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MATE transporters are best characterized in excretory organs such as kidney and liver but so far overlooked in the placenta. In the proximal tubules of the kidney as well as in hepatocytes, vectorial transport across the basolat-eral and apical membrane has been described in which OCTs mediate the cellular uptake of cationic compounds across the basolateral membrane while MATE mediate the efflux across the apical membrane (Giacomini et al., 2010). So in the kidney, excretion of organic cations is sup-posed to be mediated by the efficient interplay between OCT2 and MATE1/MATE2-K in renal tubular epithelial cells (Yonezawa & Inui, 2012) while in the liver, the excre-tory process is mediated by collaboration between OCT1 and MATE1 (Ciarimboli, 2008). In our recent study, we assumed a similar interplay between OCT3 and MATE1 and/or MATE2 might occur also in the placenta (Ahmadimoghaddam et al., 2012). Using the technique of dually perfused rat term placenta we demonstrated that Oct3, in a concentration-dependent manner, takes up organic cations from the fetal circulation into the placenta and Mate1 is responsible for their efflux to the maternal circulation. We speculate, that the H+ gradient inevitable for MATE function in the syncytiotrophoblast is provided by an ATP-driven H+ pump (Simon et al., 1992) and/or by Na+/H+ exchangers (Sibley et al., 2002)that have been localized in the placenta of several spe-cies as important mechanisms for syncytiotrophoblast homeostasis. We proposed that Oct3 and Mate1 form an efficient transplacental eliminatory pathway for organic cations and play an important role in fetal protection and detoxication (Ahmadimoghaddam et al., 2012). To date, placental expression of MATE1/Mate1 has been described only in the rat; no MATE1/Mate1 mRNA was detected in murine (Aleksunes et al., 2008; Lickteig et al., 2008) and human term placenta (Otsuka et al., 2005). However, our preliminary findings (Ahmadimoghaddam & Staud, unpublished data) indicate, that human pla-centa of the first trimester does express MATE1; further studies are required to explain the OCT3-MATE1 elimi-natory pathway in the human placenta.
Since OCTs and MATEs collaborate in transporting their substrates through polarized cells, it is obvious that an extensive overlap must exist between these two transporter families in substrates and inhibitors. Indeed, many common substrates of OCTs and MATEs have been described, including endogenous molecules (e.g. corticos-terone, estradiol, progesterone, dopamine, epinephrine, histamine, and serotonin), drugs in clinical use (e.g. acy-clovir, metformin, procainamide, imipramine, diltiazem, quinine, amantadine, cimetidine, and topotecan) as well as other toxins and environmental pollutants (e.g. cocaine, paraquat, ethidium, and nicotine) (Nies et al., 2011). Considering the number of substrates and inhibitors, it is very likely that drug–drug interactions or disruption of the OCT/MATE-mediated eliminatory pathway will affect the transplacental pharmacokinetics of these substrates and limit the detoxication capacity of the placenta.
concentrative and equilibrative nucleoside transporters (cNts, eNts)
Nucleosides are usually hydrophilic molecules that require specific transport protein(s) to be translocated across biological membranes. Two classes of nucleo-side transporters have been described, i.e. concentra-tive nucleoside transporters (CNT) and equilibrative nucleoside transporters (ENT) encoded by SLC28 and SLC29 genes, respectively (Molina-Arcas et al., 2008). Their expression has been confirmed in various organs and cell types where they are believed to mediate cell uptake of natural nucleosides and thus regulate essential physiological functions. In addition, it can be presumed, that these transporters may have a substantial role in the pharmacokinetics of most nucleoside-derived drugs used in anticancer and antiviral therapies (Klaassen & Aleksunes, 2010). Nucleoside transporters are also known to interact with toxins such as caffeine and nicotine (Lang et al., 2004), compounds with recognized harmful effect on placental/fetal development. Several ENT and CNT transporters have been localized in the placenta (Griffiths et al., 1997a; Griffiths et al., 1997b; Leazer and Klaassen, 2003; Baldwin et al., 2005; Govindarajan et al., 2007; Errasti-Murugarren et al., 2011) and human syn-cytiotrophoblast-derived cell lines BeWo, JEG3 and JAr (Yamamoto et al., 2007; Govindarajan et al., 2009). These human cell lines and conditionally immortalized rat tro-phoblast cells have been recently employed to study the role of nucleoside transporters in placental disposition of nucleoside-based drugs such as 6-mercaptopurine (Lee et al., 2011), 2',3'-dideoxyinosine (Sato et al., 2009), zidovudine (Nishimura et al., 2008; Sai et al., 2008), and ribavirin (Yamamoto et al., 2007).
To explain the role of nucleoside transporters in placental physiology and pharmacology, Errasti-Murugarren et al. (2011) comprehensively investigated the expression, activity, and subcellular localization of nucleoside transporters in human syncytiotrophoblast (Errasti-Murugarren et al., 2011). They showed that CNT1, CNT2, CNT3, ENT1, and ENT2, as well as the recently characterized spliced isoform of CNT3 were expressed in human placenta, of which CNT1, ENT1, and ENT2 were functionally expressed in the maternal-facing side of the syncytiotrophoblast and ENT2 together with CNT1 were shown to be functional also in the basal mem-branes; functional expression of CNT2 and CNT3 was ruled out in human term placentas. The authors specu-late that apical and basal CNT1 mediates the pyrimidine nucleoside supply to the placenta from both maternal and fetal circulations and the transporter thus plays a crucial role in promoting pyrimidine salvage and placen-tal growth (Errasti-Murugarren et al., 2011). Considering that some nucleoside-derived drugs (anticancer, anti-viral) and xenobiotics (nicotine, caffeine) interact with placental CNT1, it is reasonable to assume that most of the harmful effects generated by these compounds can be mediated by their inhibition of CNT1, thus impairing
the pyrimidine nucleoside salvage process (Errasti-Murugarren et al., 2011).
effect of drug transporters on transplacental pharmacokinetics
In the transfer of drugs across the placenta, both pas-sive diffusion and transporter-facilitated forms of transports are involved. The majority of clinically used drugs are lipid-soluble molecules, thus passive diffu-sion is the most common way of their transplacental passage. However, with the accumulating evidence on drug transporters in the placenta and the number of their recognized substrates and inhibitors, it is evident that placental transport proteins play a critical role in materno-fetal disposition of drugs. The net placental transport is then given by combination of passive dif-fusion and transporter-mediated transfer (Figure 5). To quantify transplacental passage of drugs and to evaluate the role of drug transporters in this event, we have recently proposed a pharmacokinetic model that discriminates between passive diffusion and
transporter-mediated transport across the placenta (Staud et al., 2006; Cygalova et al., 2009). Passive diffu-sion of a drug across the placenta is typically governed by Fick´s law and, therefore, depends on physical-chemical properties of the molecule, surface area and thickness of the placenta, and transplacental concen-tration gradient. On the other hand, transporter-medi-ated transfer is a capacity-limited event that can be described by Michaelis-Menten kinetics. Both types of transport can be expressed by means of drug clearance, that is, clearance of passive diffusion (Cl
pd) and clear-
ance of transporter-mediated process (Cltm
). As clear-ance is an additive parameter, the total transplacental clearance is a combination of Cl
pd and Cl
tm. For exam-
ple, P-glycoprotein-mediated efflux in the placenta runs exclusively from fetus to mother. Therefore, total transplacental clearance of a lipid soluble substrate of P-glycoprotein in the fetal-to-maternal direction (Cl
fm)
will be calculated by adding the two particular clear-ances as follows:
Cl Cl Clfm pd tm= + (1)
Figure 5. Role of efflux transporters in drug transport across the placenta; effect of lipid - solubility. Transport of drugs across the placenta is a function of passive and transporter-mediated processes. ABC efflux transporters are mainly localized to the apical, mother-facing membrane and pump their substrates from placenta to maternal circulation. These transport proteins, therefore, limit mother-to-fetus and accelerate fetus-to-mother transport of xenobiotics, thus, forming functional part of the placental barrier. In the case of hydrophilic/charged compounds, the role of passive diffusion is rather limited and the transporter-mediated clearance plays a great role in the transplacental pharmacokinetics. On the other hand, lipid solubility may overshadow the role of active transport; consequently, highly lipophilic compounds are transported mainly by passive diffusion and their transplacental pharmacokinetics is not significantly affected by placental efflux transporters. See text for explanation.
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On the other hand, in the maternal-to-fetal direction (Cl
mf), P-glycoprotein-mediated transport is subtracted
from passive diffusion:
Cl Cl Clmf pd tm= − (2)
In the clearance concept, transplacental passage mediated by a transport protein can be expressed as follows:
Cltmm ma fa
=+ ( )
V
K Cmax
(3)
where Vmax
is the maximal velocity of the transport, Km
is the concentration at which half the maximal velocity is reached, and C
ma(fa) is substrate concentration in the
maternal (Cma
) or fetal (Cfa
) circulation. Adding equation (3) to (1) and (2) yields the final formulas describing total transplacental clearance in fetal to maternal (Cl
fm) and
maternal-to-fetal (Clmf
) directions:
Cl Clfm pdm f
= ++
V
K C a
max
(4)
and
Cl Clmf pdm m
= −+
V
K C a
max
(5)
In the case of drug efflux transporters, it can be assumed that these will show noticeable effect in trans-placental pharmacokinetics and fetal protection only if the rate of Cl
tm is considerable in comparison to Cl
pd. If
a drug is highly lipid soluble, Clpd
will be substantially larger than Cl
tm and, subsequently, transporter activity
will be overwhelmed by the passive diffusion and will have negligible effect on transplacental pharmacokinet-ics (Figure 5). We have recently confirmed this assump-tion in a study using various P-glycoprotein and BCRP substrates and concluded that rise in lipid solubility increases the passive diffusion and, at the same time, decreases the efflux transporter effectiveness. Even in the case of BODIPY FL prazosin, a dual substrate of both P- glycoprotein and BCRP, the combined effect of both transporters was suppressed by high lipid solubility of the molecule and, therefore, rapid clearance by passive diffusion (Cygalova et al., 2009).
On the other hand, placental transport of drugs that show slow passive diffusion will be greatly affected by transporter activity and, therefore, might be prone to transporter malfunctioning, such as inhibition, down-regulations, drug interactions or polymorphisms.
clinical impact; pharmacotherapy during pregnancy
As stated in the introduction, many situations exist in which pregnant women are transiently or con-tinuously medicated. The most widely used drugs in gestation include, but are not limited to, analgesics, anti-depressives, antihistamines, antiemetics, hypoglycemics,
antiasthmatics, antiepileptics, antibiotics, antivirals, and diuretics (Bonati et al., 1990). Drugs are generally not tested for use during pregnancy and are, therefore, used off-label without detailed information on dosing and fetal and maternal safety. Obviously, inappropriate dosing can result in inadequate treatment of the mother or developmental toxicity of the fetus. Here we address two clinical situations of pharmacotherapy during preg-nancy: (i) treatment of the mother where her fetus should stay out of the reach of the drug and the transplacental passage is not appreciated as well as (ii) transplacental treatment of the fetus where transport of the drug across the placenta is mandatory. Transplacental pharmaco-therapy of fetal diseases is a relatively novel discipline of noninvasive medicine in which the mother is adminis-tered a drug that, after transplacental transport, reaches fetal circulation to fulfill its mission. To maximize fetal drug exposure (and therefore drug effectiveness) and to minimize drug activity/toxicity in the mother remains a challenging task.
Detailed knowledge on the transplacental pharma-cokinetics and the role of placental drug transporters should help in optimizing transplacental treatment and choosing the right drugs and dosage algorithms. In addi-tion, pharmacological regulation of placental transporter activity has become a new possibility to upgrade phar-macotherapy of the fetus. In the following section, we specifically focus on four situations in which pregnant women need to take medication frequently and regularly throughout the whole period of pregnancy to treat them-selves or their fetus, i.e. epilepsy, diabetes, HIV infection and fetal arrhythmias. We have chosen these conditions as they are often treated by co-administration of two or more compounds that are substrates of placental drug transporters.
transplacental pharmacotherapy of fetal arrhythmias
Most fetal heart arrhythmias occur only transiently and do not present significant risk to the fetus. However, several forms of sustained fetal heart arrhythmias are observed in about 1% of all pregnancies (Villain et al., 1990) with considerable hazard for the fetal develop-ment. For example, fetal supraventricular tachycardia may cause intrauterine congestive heart failure with hydrops fetalis which is a potentially life-threatening con-dition for the unborn (Kleinman et al., 1985). Since the outburst of prenatal diagnostics in the 1980s, the impor-tance of managing fetal arrhythmias has been increasing continuously.
Nowadays, the treatment of fetal arrhythmias usu-ally consists of the transplacental administration of digoxin as the drug of first choice (Maeno et al., 2009). If digoxin fails to achieve conversion to sinus rhythm it is followed by, or combined with, sotalol, flecainide, amio-darone, verapamil or other antiarrhythmic agents (Ito, 2001; Singh, 2004; Lulic Jurjevic et al., 2009). Although
transplacental passage of digoxin, flecainide, and amio-darone has been confirmed using the technique of ex vivo perfused human term placenta (Schmolling et al., 2000), in vivo data indicate rather low umbilical cord to maternal plasma drug concentration ratio of these com-pounds with considerable interindividual variability. In detail, fetal-to-maternal drug concentration ratio ranges between 0.1–0.9 for digoxin, 0.5–0.9 for flecainide (Ito, 2001), 0.1–0.6 for amiodarone (Widerhorn et al., 1987) and 0.1–0.2 for verapamil (Widerhorn et al., 1987). It can be speculated that the low drug concentrations in the fetal umbilical vessels may, at least partly, be caused by placental drug transporters. Indeed, most of the car-diovascular drugs have been described as substrates of one or more drug transporters; digoxin is a well-known substrate of P-glycoprotein and some OATP isoforms, flecainide is a substrate and inhibitor of OCT1, OCT2 and OCT3 and amiodarone is a substrate of OCT1, OCT2, OCT3, MATE1 and MATE2 (for details see comprehen-sive reviews by (Cascorbi, 2011; Keppler, 2011; Nies et al., 2011)). Similarly, other cardiovascular drugs used in transplacental treatment of fetal arrhythmias, such as verapamil and quinidine, are substrates of various drug transporters (Cascorbi, 2011; Keppler, 2011; Nies et al., 2011) and clinically important pharmacokinetic interac-tions between cardiovascular drugs, mainly digoxin, have been reported (Nademanee et al., 1984; Kodawara et al., 2002; Lee et al., 2010; Glaeser, 2011). It is thus feasible to assume that drug transporters in the placenta decrease mother-to-fetus transport of these cardiovascular drugs and enable drug–drug interactions.
Several reports have been published in which failed maternal therapy with digoxin alone was followed by combined therapy with amiodarone (Pradhan et al., 2006) or quinidine (Spinnato et al., 1984). These combi-nations lead to conversion to sinus rhythm and resolu-tion of hydrops. We believe that the improved outcome of combined therapy is not only due to pharmacody-namic potentiation. We assume that co-administration of drugs that are substrates and/or inhibitors of drug transporters (such as P-glycoprotein) may lead to various pharmacokinetic interactions throughout the maternal organs including the placenta: (i) competition for drug efflux transporters within the maternal excretory organs, kidney and liver, that results in inhibition of transporter-mediated drug excretion and subsequent increase in drug concentrations in maternal plasma and (ii) drug interactions on the placental transporters that may result in transporter inhibition and greater drug penetration across the placenta to the fetus. For example, verapamil increases digoxin serum concentrations by inhibiting P-glycoprotein-mediated digoxin excretion; in addition, in the treatment of fetal arrhythmias, co-administered verapamil may enhance digoxin transfer into fetus by blocking placental P-glycoprotein (Ito, 2001).
Sotalol, on the other hand is a compound with limited affinity to drug transporters; it has been suggested to be a P-glycoprotein substrate, however, with questionable
clinical significance (Liu et al., 2012). This fact, along with its low protein binding, could be the reason for sotalol being completely transported across the placenta from mother to fetus reaching equal concentrations in maternal and fetal compartments at steady state (O'Hare et al., 1980; Oudijk et al., 2003). In view of transplacental pharmacokinetics, sotalol is a good candidate for trans-placental treatment of fetal arrhythmias as its passage across the placenta is rather predictable; indeed, there are indices of its preferred use to digoxin (Shah et al., 2012).
treatment of HIv infection in pregnant women
Infection of pregnant women with human immunodefi-ciency virus (HIV) is a specific situation, in which both the mother and her fetus are the targets of pharmacother-apy. The current approach to prevent mother-to-child transmission of HIV consists of highly active antiretroviral therapy (HAART) which is a combination of at least two nucleoside/nucleotide inhibitors of reverse transcriptase (NRTIs) together with one protease/non-nucleoside reverse transcriptase inhibitor (PI/NNRTI) that affect dif-ferent steps of viral replication cycle. HAART was shown to successfully decrease the rate of child infection from 20–45% to less than 1% (De Cock et al., 2000).
Many of NRTIs/NNRTIs have been shown to interact with both ABC and SCL drug transporters (see Tables 1 and 2); nevertheless, most of these compounds pass the placental barrier relatively easily with cord concentra-tions reaching similar values to those found in mother (Liebes et al., 1990; Havlir et al., 1995; Bloom et al., 1997; Bawdon, 1998; Mirochnick et al., 1998; Moodley et al., 1998; Musoke et al., 1999; Chappuy et al., 2004; Hirt et al., 2009; Flynn et al., 2011). The role of placental transport-ers in the fetal exposure of reverse transcriptase inhibi-tors thus remains questionable.
In contrast, transplacental passage of protease inhibi-tors is generally very limited with cord-to-mother concen-tration ratios reaching approximately 0–0.2 for ritonavir, 0–0.1 for lopinavir (Marzolini et al., 2002), and less than 0.3 for nelfinavir, saquinavir, and indinavir (Marzolini et al., 2002; Chappuy et al., 2004; Gedeon & Koren, 2006). This can, at least partly, be explained by affinity of prote-ase inhibitors to placental ABC and/or SLC transporters (Smit et al., 1999; Sudhakaran et al., 2008).
Several antiretroviral drugs have the potency to modulate (inhibit) drug transporters of both ABC and SLC families. For example NRTIs, efavirenz, nevirapine, abacavir and tenofovir disoproxil fumarate have been reported to inhibit P-glycoprotein (Storch et al., 2007); abacavir, nevirapine, and efavirenz were also described to inhibit BCRP (Weiss et al., 2007). Emtricitabine, abacavir, zidovudine, and tenofovir disoproxil fumarate showed efficient inhibition of OCT1, OCT2, and OCT3 (Minuesa et al., 2009). Protease inhibitors, in general, seem to be very potent inhibitors of drug transporters: nelfinavir,
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ritonavir, lopinavir, saquinavir, amprenavir, indinavir, and atazanavir are potent blockers of P-glycoprotein (Storch et al., 2007; Bierman et al., 2010); lopinavir, nelfinavir, saquinavir, atazanavir, and amprenavir decrease efflux activity of BCRP (Weiss et al., 2007); ritonavir, saquinavir, indinavir, and lopinavir have been shown to inhibit OCT1 and OCT2 (Zhang et al., 2000; Kis et al., 2009). OATP1A2 and/or OATP2B1 transport function can be decreased by lopinavir, ritonavir, saquinavir, indinavir, and nelfinavir (Kis et al., 2009). It can be expected that many other inter-actions between antiretroviral agents and drug transport-ers (transport/inhibition) are yet to be revealed.
Drug–drug interactions of antiretrovirals on drug transporters thus represent an important issue for phar-macokinetic/pharmacodynamic modifications of HAART effectiveness. For example, ritonavir is often included in HAART not only for its own antiviral activity, but also for its capacity to inhibit drug efflux by ABC transporters as well as drug metabolism by CYP450 enzymes (Gulati & Gerk, 2009). This inhibition results in higher bioavail-ability, slower elimination and thus increased concentra-tions of concomitantly administered drugs. In addition, when administered in pregnant woman, we can specu-late that ritonavir may inhibit placental ABC transport-ers (P-glycoprotein, BCRP) and, therefore, increase fetal exposure to other HAART components. In clinical trials, it has been demonstrated that co-administration of ritona-vir with indinavir results in pharmacokinetic interactions that allow for reduced dosage of both drugs (Hsu et al., 1998). Moreover, as even low-dose ritonavir increases plasma concentrations of co-administered indinavir, this combination has been tested as a new medication scheme in children to increase their adherence to indina-vir-containing HAART (Fraaij et al., 2007). Bousquet and colleagues (2008) demonstrated that combined admin-istration of emtricitabine with tenofovir and efavirenz (Atripla®) results in higher intracellular concentrations of tenofovir as well as emtricitabine. The authors speculate this phenomenon is, at least partly, caused by inhibition of MRP family of ABC transporters (Bousquet et al., 2008). In another study, Minuesa et al. proposed that inhibition of OCTs mediated by abacavir and zidovudine might have important clinical implications especially with regard to lamivudine pharmacokinetics (Minuesa et al., 2009).
Given the wide spectrum of antiretroviral drugs and their interactions with various drug transporters, it is reasonable to predict that many more drug–drug inter-actions, either advantageous or disadvantageous during HAART treatment will be revealed in the near future. Proper knowledge of these pharmacological aspects should enable the clinicians to exploit or avoid these interactions in order to achieve adequate drug levels in both maternal and fetal circulations.
treatment of epilepsy in pregnant women
Epilepsy is a relatively common complication that affects 0.3–0.5 % of all pregnant women (Viinikainen et al., 2006).
In the USA, up to 1.1 million women with epilepsy are of child-bearing age and give birth to over 20,000 babies each year (Feghali & Mattison, 2011). When uncontrolled dur-ing pregnancy, seizures may result in maternal trauma, placental abruption or fetal hypoxia and are potentially life-threatening for both mother and fetus. Many antiepi-leptic drugs (AEDs) are administered during pregnancy to prevent seizures in mother; however, at the same time the treatment is potentially associated with significantly higher occurrence of fetal abnormalities and develop-mental disorders especially when used in polytherapy (Tomson & Battino, 2009; Holmes et al., 2011; Vajda et al., 2011; Hernandez-Diaz et al., 2012). Thus, the ultimate aim of epilepsy treatment during pregnancy is a monotherapy leading to seizure-free mother and toxicity-free fetus. Nevertheless, to date, such an antiepileptic agent or treat-ment regimen has not been found.
Many AEDs are substrates of drug efflux transporters (Loscher & Potschka, 2005) and it is believed that fetal exposure to AEDs may be affected by drug-transporting proteins in the placenta. However, it must be remem-bered, that the treatment of CNS diseases (including epi-lepsy) during pregnancy is complicated by the fact, that the compounds must cross the blood–brain barrier (BBB) to fulfill their therapeutic potential. BBB is one of the tightest and most complex of body barriers and, therefore, the compounds are generally small and very lipophilic in nature. It is safe to assume that a compound capable of crossing the blood–brain barrier will easily penetrate the placenta as well. It can hardly be expected that drug efflux transporters will have a significant effect on pla-cental transport of these drugs since their high lipid-solubility and fast passive diffusion surpass the effect of transporter-mediated efflux (as shown in Figure 5). Accordingly, placental perfusion studies have shown that most AEDs (e.g. carbamazepine, oxcarbamazepine, phe-nytoin, primidone, and lamotrigine), regardless of their affinity to P-glycoprotein, cross the placenta in substantial amounts, and the fetal concentrations are equal or even higher than those in the maternal circulation (Myllynen & Vahakangas, 2002; Myllynen et al., 2005). The only excep-tion here is valproic acid, a low molecular weight fatty acid that is completely ionized at physiological pH. It is obvious that the compound cannot cross biological mem-branes by passive diffusion, yet it shows potent transpla-cental transfer (Ishizaki et al., 1981). The mechanism of passage of valproic acid across the placenta has not been explained satisfactorily so far. Using in vitro models of human placental choriocarcinoma cell line (BeWo) and human placental brush-border membrane vesicles it has been proposed that the transplacental passage of valproic acid is mediated by a proton-linked saturable transport system, including the family of monocarboxylic acid transporters (Utoguchi & Audus, 2000; Ushigome et al., 2001; Nakamura et al., 2002).
Lamotrigine is a third generation AED that has been demonstrated by pregnancy registries to be one of the safest medications for treatment in pregnancy due to low
occurrence of fetal malformations and uncomplicated cognitive development after birth (Tomson & Battino, 2009; Holmes et al., 2011; Hernandez-Diaz et al., 2012). Therefore, it is considered the drug of first choice for women planning pregnancy (Moore & Aggarwal, 2012). Lamotrigine is rapidly transferred across the perfused human placental cotyledon, reaching similar values in fetal and maternal circulations (Myllynen et al., 2003). When given in monotherapy, the ratio of lamotrigine concentration between newborn and mother ranged from 0.40 to 1.38 (Kacirova et al., 2010) suggesting great interindividual variability, most likely due to variable expression of phase 2 metabolizing enzymes in the placenta and/or genetic polymorphism of glucuronyl-transferase UGT2B7 (Collier et al., 2002). It is therefore possible, that not only placental transporters but also biotransformation enzymes may affect transplacental passage and fetal drug exposure.
There are several possibilities to limit placental trans-port of AEDs:
Barzago et al. encapsulated valproic acid into lipo-somes as drug carriers in an attempt to decrease mother-to-fetus passage of the molecule (Barzago et al., 1996). They confirmed this modification significantly reduced the fetal exposure to valproic acid; however it is feasible to assume that such an alteration will lower also the passage of valproic acid across the BBB and might, therefore, com-promise its brain exposure and anticonvulsant activity.
Brain-targeting by intranasal administration offers yet another possibility to ensure safe treatment of epilepsy (and other CNS diseases) in pregnancy. Drugs adminis-tered through this route “take a shortcut” from the olfac-tory region directly to the central nervous system without prior absorption to the systemic circulation. This neuro-nal connection was found to constitute a direct pathway to the brain, bypassing the BBB (Illum, 2000; Garcia-Garcia et al., 2005) as observed in the case of several CNS active drugs such as carbamazepine (Barakat et al., 2006) or morphine (Westin et al., 2006). In addition, Eskandari et al. (2011) have recently incorporated valproic acid in nanostructured lipid carriers and observed high brain/plasma concentration ratio after intranasal delivery (Eskandari et al., 2011). We, therefore, propose that spe-cific delivery systems for intranasal drug administration will ensure lower plasma concentrations of the drug, thus present reduced risk of materno-fetal transport across the placenta and fetal toxicity.
Finally, considering current knowledge on distribu-tion and substrate specificity of drug transporter it seems logical, that a substrate of an uptake transporter that is oriented in blood-to-brain and fetus-to-mother direction (e.g., some of OATs, OCTs, OATPs) may fulfill the require-ment for enhanced delivery of antiepileptic compounds to the brain while keeping mother-to-fetus passage across the placenta to minimum. These transporters thus might represent novel therapeutic targets not only for epilepsy, but other CNS diseases commonly treated in pregnancy, such as depression.
treatment of gestational diabetes mellitus
Gestational diabetes mellitus (GDM) is defined as ‘any degree of glucose intolerance with onset or first recogni-tion during pregnancy’ that complicates gestation and presents a risk of long-term diabetes in both the mother and offspring (Ben-Haroush et al., 2004). GDM devel-ops in about 5% of pregnant women with increasing prevalence; it is assumed these figures may reach up to 20%, mostly in obese women (Gauster et al., 2012). The management of GDM consists mainly of diet and life-style modification; when these approaches fail to restore normoglycemia, insulin is the drug of choice. However, insulin treatment has been associated with several limitations, such as immune response, hypoglycemia, weight gain, as well as the need to educate the patient. In addition, pain and discomfort connected with insu-lin administration complicate the treatment and may lead to non-compliance (Gedeon & Koren, 2006). Low-molecular oral hypoglycemic agents are, therefore, still searched for as a “more comfortable” alternative and, indeed, recent evidence based on trials and meta-analy-ses shows that GDM can be safely and effectively treated with oral hypoglycemic agents such as glyburide or met-formin (Rowan et al., 2008; Nicholson et al., 2009; Waugh et al., 2010; Renda et al., 2011). Both of these agents are recognized substrates of various drug transporters (see Tables 1 and 2) and their materno-fetal transport is, therefore, largely controlled by levels of expression of placental transporters.
Glyburide (also known as glibenclamide), a second generation sulfonylurea agent that increases secretion of endogenous insulin, appears to be a good candidate for GDM treatment (Coustan, 2007) as it only insignificantly crosses the human placenta (Elliott et al., 1991; Elliott et al., 1994; Langer et al., 2000). The low transplacental permeability of glyburide was originally attributed to very extensive plasma protein binding coupled with a short elimination half-life (Koren, 2001; Nanovskaya et al., 2006a). However, using in vitro perfusions of a human placental cotyledon, Kraemer et al. (2006) observed that glyburide was actively transported from fetus to mother by a transporter other than P-glycoprotein (Kraemer et al., 2006). Shortly afterwards, the involvement of BCRP in the active efflux of glyburide in the feto-maternal direc-tion was identified using in vitro brush border human placental vesicles (Gedeon et al., 2008), ex vivo perfusion of human placental cotyledons (Pollex et al., 2008) and in vivo in the Bcrp1(-/-) pregnant mice (Zhou et al., 2008). We further demonstrated the ability of placental BCRP not only to hinder the maternal-to-fetal penetration of glyburide, but even to accelerate the feto-maternal trans-port of glyburide in a concentration-dependent manner (Cygalova et al., 2009). Glyburide, thus, seems to posses ideal pharmacokinetic properties (i.e. affinity to drug efflux transporter, high plasma protein binding and short elimination half-life) that preclude its transplacental transport.
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Metformin, a biguanide derivative, has for long been considered to be non-teratogenic (Coetzee & Jackson, 1979; Coetzee & Jackson, 1984; Coetzee & Jackson, 1985); however, the recommendation for the use of metformin in pregnancy was introduced with-out proper knowledge of its transplacental passage and effects on fetus. In a recent randomized controlled open trial of 751 women with gestational diabetes, Rowan et al. (2008) evaluated the efficiency and safety of insulin versus metformin treatment. Comparing out-comes such as maternal and neonatal hypoglycemia, respiratory distress, birth trauma, Apgar score, pre-maturity, neonatal anthropomorphic measurements, postpartum glucose tolerance, and acceptability of treatment the authors reported no significant differ-ences between the metformin and insulin groups. In addition, the women preferred metformin treatment to insulin (Rowan et al., 2008).
Regarding metformin affinity to drug transporters, this compound is a well-recognized substrate of many SLC proteins, including influx OCT1, OCT2 and OCT3 and efflux MATE1 and MATE2 transporters (Table 2). Considering functional expression of OCT1 and OCT3 in the human placenta, their role in transplacental phar-macokinetics of metformin can be expected. Several research groups used dually perfused ex vivo placental cotyledon model to study transport of metformin across the placenta, however, with differing results. Kovo et al., (2008a) reported that the transplacental clearance index for metformin was quite low (0.34 ± 0.05) (Kovo et al., 2008a) and only slightly higher than that of glyburide (0.21 ± 0.09) (Elliott et al., 1994). Subsequently the same team suggested that metformin permeability across the placenta is mediated by a carrier transporting cationic compounds bi-directionally, with a higher transfer rate from the fetal to the maternal side (Kovo et al., 2008b). On the other hand, other teams reported on fast trans-placental passage of metformin from mother to fetus without transporter involvement (Nanovskaya et al., 2006b; Tertti et al., 2010). Unfortunately, all these stud-ies failed to investigate dose-dependent pharmacoki-netics of metformin passage across the placenta, which is an essential approach to reveal transporter-mediated and saturable process. In addition, none of these reports considered a second transporter for vectorial movement across the placenta; as discussed previously, OCTs can only uptake their substrates into the cells but another transporter is responsible for drug efflux (Figures 3 and 4). In the rat placenta, we demonstrated that metformin is transported from fetus to mother by Oct3/Mate1 vectorial transport (Ahmadimoghaddam and Staud, unpublished data). In addition, Hemauer et al., (2010) suggested the transport of metformin might be affected by P-glycoprotein and BCRP trans-porters in the placental brush border vesicles (Hemauer et al. 2010). However, further studies are needed to confirm the efflux of metformin from the trophoblast cells to mother.
conclusions, limitations, perspectives
Ethical and technical obstacles to clinical research in pregnant women hinder the progress at which relevant in vivo data is obtained; therefore our knowledge on drug disposition during pregnancy is based on experi-mental approaches trying to mimic the pregnancy sta-tus. Furthermore, most of the information on placental transport has been collected from the final phases of pregnancy, thus reflecting the conditions of the term placenta. Little is known about earlier stages of gestation which is a period of organogenesis carrying the biggest risk of drug-induced malformations and teratogenic-ity. Placenta has been reported to be more permeable toward the term for drugs that can pass the placenta by the mechanism of passive diffusion (Coan et al., 2008). In addition, expression and function of placental drug transporters varies greatly throughout pregnancy; there-fore placental barrier function and fetal drug exposure is believed to change with gestational age (Feghali & Mattison, 2011). For example, the transplacental transfer of methadone from mother to fetus was reported to be significantly higher in term compared to preterm placen-tas (Nanovskaya et al., 2008), which correlates well with the lower expression of placental P-glycoprotein at term. Importantly, final fetal exposure will also be determined by functional expression of transporter and biotransfor-mation proteins in the fetal tissues (Cygalova et al., 2008), which is an area largely unexplored. With current body of information, it is thus difficult to predict fetal drug expo-sure at earlier stages of pregnancy.
Transport of drugs across the placenta is only one stone in the complex mosaic of pharmacokinet-ics in the pregnant women. Pregnancy is a dynamic state accompanied with many changes in physiology such as body composition, total body water and fat, distribution volume, cardiac output, kidney and/or liver excretion; these changes in turn affect drug dis-position in the maternal organism (Pavek et al., 2009; Feghali & Mattison, 2011). A number of mathematical approaches, mainly physiologically-based pharma-cokinetic (PBPK) models, have been developed over the last three decades to assess the pharmacokinetics of drugs throughout pregnancy, taking into account changes in maternal-placental-fetal anatomy and physiology. Although many of these models included drug metabolism, placental drug transporters have not been considered so far (Lu et al., 2012). Abduljalil and colleagues have recently gathered essential time-vari-ant anatomical, physiological and biological param-eter values and created a comprehensive database for parameters required in PBPK models defining preg-nancy (Abduljalil et al., 2012). The authors further for-mulated algorithms describing the average changes in parameter values and their variability with gestational age. This approach might help assess the quality of pharmacotherapy and predict the risk of intoxications in the pregnant women and her developing fetus.
Many genetic polymorphisms have been described in the placental drug transporters and many others are yet to be revealed (Kobayashi et al., 2005; Atkinson et al., 2007; Hutson et al., 2010; Pollex et al., 2010; Pollex & Hutson, 2011; Ieiri, 2012). In addition, pathological con-ditions, such as cholestasis, might affect expression of placental drug transporters of both ABC and SLC families (Serrano et al., 2003). It is evident, that these intra- and interindividual variations will further obscure prediction of fetal drug exposure.
One of the most complicated circumstances of phar-macotherapy in pregnancy is the treatment of CNS disor-ders, such as epilepsy or depression. In these situations, the drug(s) must cross the blood–brain barrier and are, therefore, likely to cross the placenta easily as well. As discussed in the section regarding epilepsy treatment, novel drug designs and delivery systems will be searched for. For example, intranasal administration of drugs has the advantage of bypassing the blood–brain barrier while minimizing systemic exposure (Dhuria et al., 2010; Liu, 2011; Gomez et al., 2012), which would be an ideal approach for treatment of neurological disorders in preg-nant women.
We believe that not only clinicians, but also research-ers in the pharmaceutical industry will profit from detailed knowledge on tissue distribution and substrate specificity of drug transporters in the placenta and these proteins will become novel therapeutic targets for con-trolled drug delivery across the placenta.
Declaration of interest
This work was supported by Czech Science Foundation [GACR P303/12/0850].
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762 F. Staud et al.
Journal of Drug Targeting
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