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The Placental Barrier: the Gate and the Fate in Drug Distribution

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  • Theme: The Use of Pharmaceuticals in Pregnancy and Lactation
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Abstract

Optimal development of the embryo and the fetus depends on placental passage of gases, nutrients, hormones, and waste products. These molecules are transferred across the placenta via passive diffusion, carrier-mediated cellular uptake and efflux, and transcytosis pathways. The same mechanisms additionally control the rate and extent of transplacental transfer of drugs taken by the pregnant mother. Essentially all drugs cross the placenta to a certain extent, and some accumulate in the placenta itself at levels that can even exceed those in maternal plasma. Hence, even drugs that are not efficiently transferred across the placenta may indirectly affect fetal development by interfering with placental function. In this article, we describe key properties of the placental barrier and their modulation by medications. We highlight implications for pharmacotherapy and novel approaches for drug delivery in pregnant women and their fetuses.

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Abbreviations

ABC:

Adenosine triphosphate binding cassette

BBMVs:

Placental brush-border membrane vesicles

BCRP:

Breast cancer resistance protein

CNT:

Concentrative nucleoside transporter

CYP:

Cytochrome P-450

ENT:

Equilibrative nucleoside transporter

FcRn:

Neonatal Fc receptors

LAT:

L-type amino acid transporter

MDR:

Multidrug resistance protein

MRP:

Multidrug resistance-associated protein

NET:

Norepinephrine transporter

OAT:

Organic anion transporter

OATP:

Organic anion transporting polypeptide

OCT, OCTN:

Organic cation transporter

P-gp:

P-glycoprotein

RFC:

Reduced folate carrier

SERT:

Serotonin transporter

SLC:

Solute carrier

UGT:

Uridine diphosphate glucoronosyltransferase

References

  1. Dally A. Thalidomide: was the tragedy preventable? Lancet. 1998;351:1197–9.

    Article  CAS  PubMed  Google Scholar 

  2. Barker RH. Placental transfer of sulfanilamide. N Engl J Med. 1938;41:219.

    Google Scholar 

  3. Speert H. Passage of sulfanilamide through human placenta. Bull Johns Hopkins Hosp. 1938;63:337–9.

    CAS  Google Scholar 

  4. Ginsburg J. Placental drug transfer. Annu Rev Pharmacol. 1971;11:387–408.

    Article  CAS  PubMed  Google Scholar 

  5. Grumbach MM, Werner SC. Transfer of thyroid hormone across the human placenta at term. J Clin Endocrinol Metab. 1956;16:1392–5.

    Article  CAS  PubMed  Google Scholar 

  6. Sandler M, Ruthven CR, Contractor SF, Wood C, Booth RT, Pinkerton JH. Transmission of noradrenaline across the human placents. Nature. 1963;197:598.

    Article  CAS  PubMed  Google Scholar 

  7. Abramovich DR, Wade AP. Transplacental passage of steroids: the presence of corticosteroids in amniotic fluid. J Obstet Gynaecol Br Commonw. 1969;76:610–4.

    Article  CAS  PubMed  Google Scholar 

  8. Burton GJ, Jauniaux E. What is the placenta? Am J Obstet Gynecol. 2015;213:S6–8.

    Article  PubMed  Google Scholar 

  9. Guttmacher AE, Maddox YT, Spong CY. The human placenta project: placental structure, development and function in real time. Placenta. 2014;35:303–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maltepe E, Fisher SJ. Placenta: the forgotten organ. Annu Rev Cell Dev Biol. 2015;31:523–52.

    Article  CAS  PubMed  Google Scholar 

  11. DeVane L, Goetzl LM, Ramamoorthy S. Exposing fetal drug exposure. Clin Pharmacol Ther. 2011;89:786–8.

    Article  CAS  PubMed  Google Scholar 

  12. Goodman AG, Rall TW, Nies AS, Taylor P. Goodman and Gilman’s the pharmacological basis of therapeutics. Eighth ed. New York: Mcgraw-Hill (Tx); 2000.

    Google Scholar 

  13. Tomi M, Nishimura T, Nakashima E. Mother-to-fetus transfer of antiviral drugs and the involvement of transporters at the placental barrier. J Pharm Sci. 2011;100:3708–18.

    Article  CAS  PubMed  Google Scholar 

  14. Burton GJ, Fowden AL. The placenta: a multifaceted, transient organ. Philos Trans R Soc Lond B Biol Sci. 2015;370(1663).

  15. Huppertz B. The anatomy of the normal placenta. J Clin Pathol. 2008;61:1296–302.

    Article  CAS  PubMed  Google Scholar 

  16. Hutson JR, Garcia-Bournissen F, Davis A, Koren G. The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs. Clin Pharmacol Ther. 2011;90:67–76.

    Article  CAS  PubMed  Google Scholar 

  17. Bajoria R, Contractor SF. Transfer of heparin across the human perfused placental lobule. J Pharm Pharmacol. 1992;44:952–9.

    Article  CAS  PubMed  Google Scholar 

  18. Holcberg G, Tsadkin-Tamir M, Sapir O, Wiznizer A, Segal D, Polachek H, et al. Transfer of insulin lispro across the human placenta. Eur J Obstet Gynecol Reprod Biol. 2004;115:117–8.

    Article  PubMed  Google Scholar 

  19. van der Aa EM, Peereboom-Stegeman JH, Noordhoek J, Gribnau FW, Russel FG. Mechanisms of drug transfer across the human placenta. Pharm World Sci. 1998;20:139–48.

    Article  PubMed  Google Scholar 

  20. Reynolds F. Placental transfer of drugs. Curr Anaesth Crit Care. 1991;2:108–16.

    Article  Google Scholar 

  21. Rubinchik-Stern M, Eyal S. Drug interactions at the human placenta: what is the evidence? Front Pharmacol. 2012;3:126.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Prouillac C, Lecoeur S. The role of the placenta in fetal exposure to xenobiotics: importance of membrane transporters and human models for transfer studies. Drug Metab Dispos. 2010;38:1623–35.

    Article  CAS  PubMed  Google Scholar 

  23. Vähäkangas K, Myllynen P. Drug transporters in the human blood-placental barrier. Br J Pharmacol. 2009;158:665–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH, Ganapathy V. Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells. Biochim Biophys Acta. 1994;1223:71–5.

    Article  CAS  PubMed  Google Scholar 

  25. Staud F, Cerveny L, Ceckova M. Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure. J Drug Target. 2012;20:736–63.

    Article  CAS  PubMed  Google Scholar 

  26. Del Amo E, Urtti A, Yliperttula M. Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2. Eur J Pharm Sci. 2008;35:161–74.

    Article  PubMed  CAS  Google Scholar 

  27. Ganapathy V, Prasad PD. Role of transporters in placental transfer of drugs. Toxicol Appl Pharmacol. 2005;207:381–7.

    Article  PubMed  CAS  Google Scholar 

  28. Ni Z, Mao Q. ATP-binding cassette efflux transporters in human placenta. Curr Pharm Biotechnol. 2011;12:674–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, et al. Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science. 1986;232:643–5.

    Article  CAS  PubMed  Google Scholar 

  30. Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A. 1997;94:4028–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini KM. The UCSF-FDA transportal: a public drug transporter database. Clin Pharmacol Ther. 2012;92:545–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mathias AA, Hitti J, Unadkat JD. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am J Physiol Regul Integr Comp Physiol. 2005;289:R963–9.

    Article  CAS  PubMed  Google Scholar 

  33. Sun M, Kingdom J, Baczyk D, Lye SJ, Matthews SG, Gibb W. Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation. Placenta. 2006;27:602–9.

    Article  CAS  PubMed  Google Scholar 

  34. Hutson JR, Koren G, Matthews SG. Placental P-glycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology. Placenta. 2010;31:351–7.

    Article  CAS  PubMed  Google Scholar 

  35. Joshi AA, Vaidya SS, St-Pierre MV, Mikheev AM, Desino KE, Nyandege AN, et al. Placental ABC transporters: biological impact and pharmaceutical significance. Pharm Res. 2016;33:2847–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol. 1998;12:457–63.

    Article  CAS  PubMed  Google Scholar 

  37. Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104:1441–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eyal S, Chung FS, Muzi M, Link JM, Mankoff DA, Kaddoumi A, et al. Simultaneous PET imaging of P-plycoprotein inhibition in multiple tissues in the pregnant non-human primate. J Nucl Med. 2009;50:798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ke AB, Eyal S, Chung FS, Link JM, Mankoff DA, Muzi M, et al. Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition. J Nucl Med. 2013;54:437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Myllynen P, Vahakangas K. Placental transfer and metabolism: an overview of the experimental models utilizing human placental tissue. Toxicol in Vitro. 2013;27:507–12.

    Article  CAS  PubMed  Google Scholar 

  41. Maliepaard M, Scheffer GL, Faneyte IF, van Gastelen MA, Pijnenborg AC, Schinkel AH, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 2001;61:3458–64.

    CAS  PubMed  Google Scholar 

  42. Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, et al. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos. 2005;33:94–101.

    Article  CAS  PubMed  Google Scholar 

  43. Wang C, Xie L, Li H, Li Y, Mu D, Zhou R, et al. Associations between ABCG2 gene polymorphisms and isolated septal defects in a Han Chinese population. DNA Cell Biol. 2014;33:689–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Evseenko DA, Murthi P, Paxton JW, Reid G, Emerald BS, Mohankumar KM, et al. The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction. FASEB J. 2007;21:3592–605.

    Article  CAS  PubMed  Google Scholar 

  45. Gupta A, Dai Y, Vethanayagam RR, Hebert MF, Thummel KE, Unadkat JD, et al. Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan. Cancer Chemother Pharmacol. 2006;58:374–83.

    Article  CAS  PubMed  Google Scholar 

  46. Gupta A, Zhang Y, Unadkat JD, Mao Q. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther. 2004;310:334–41.

    Article  CAS  PubMed  Google Scholar 

  47. Pollex E, Lubetsky A, Koren G. The role of placental breast cancer resistance protein in the efflux of glyburide across the human placenta. Placenta. 2008;29:743–7.

    Article  CAS  PubMed  Google Scholar 

  48. Bakhsheshian J, Wei BR, Chang KE, Shukla S, Ambudkar SV, Simpson RM, et al. Bioluminescent imaging of drug efflux at the blood-brain barrier mediated by the transporter ABCG2. Proc Natl Acad Sci U S A. 2013;110:20801–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kumar JS, Wei BR, Madigan JP, Simpson RM, Hall MD, Gottesman MM. Bioluminescent imaging of ABCG2 efflux activity at the blood-placenta barrier. Sci Rep. 2016;6:20418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 2004;447:653–65.

    Article  CAS  PubMed  Google Scholar 

  51. Nagashige M, Ushigome F, Koyabu N, Hirata K, Kawabuchi M, Hirakawa T, et al. Basal membrane localization of MRP1 in human placental trophoblast. Placenta. 2003;24:951–8.

    Article  CAS  PubMed  Google Scholar 

  52. St-Pierre MV, Serrano MA, Macias RI, Dubs U, Hoechli M, Lauper U, et al. Expression of members of the multidrug resistance protein family in human term placenta. Am J Phys. 2000;279:R1495–503.

    Article  CAS  Google Scholar 

  53. Pascolo L, Fernetti C, Pirulli D, Crovella S, Amoroso A, Tiribelli C. Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochem Biophys Res Commun. 2003;303:259–65.

    Article  CAS  PubMed  Google Scholar 

  54. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2005;20:452–77.

    Article  CAS  PubMed  Google Scholar 

  55. Azzaroli F, Mennone A, Feletti V, Simoni P, Baglivo E, Montagnani M, et al. Clinical trial: modulation of human placental multidrug resistance proteins in cholestasis of pregnancy by ursodeoxycholic acid. Aliment Pharmacol Ther. 2007;26:1139–46.

    Article  CAS  PubMed  Google Scholar 

  56. Zeng H, Liu G, Rea PA, Kruh GD. Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 2000;60:4779–84.

    CAS  PubMed  Google Scholar 

  57. Jedlitschky G, Burchell B, Keppler D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem. 2000;275:30069–74.

    Article  CAS  PubMed  Google Scholar 

  58. Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P. Characterization and identification of steroid sulfate transporters of human placenta. Am J Physiol Endocrinol Metab. 2003;284:E390–8.

    Article  CAS  PubMed  Google Scholar 

  59. Sato K, Sugawara J, Sato T, Mizutamari H, Suzuki T, Ito A, et al. Expression of organic anion transporting polypeptide E (OATP-E) in human placenta. Placenta. 2003;24:144–8.

    Article  CAS  PubMed  Google Scholar 

  60. Obaidat A, Roth M, Hagenbuch B. The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol. 2012;52:135–51.

    Article  CAS  PubMed  Google Scholar 

  61. Tertti K, Petsalo A, Niemi M, Ekblad U, Tolonen A, Rönnemaa T, et al. Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs). Eur J Pharm Sci. 2011;44:181–6.

    Article  CAS  PubMed  Google Scholar 

  62. Grube M, Reuther S, Meyer Zu Schwabedissen H, Köck K, Draber K, Ritter CA, et al. Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta. Drug Metab Dispos. 2007;35:30–5.

  63. Ugele B, Bahn A, Rex-Haffner M. Functional differences in steroid sulfate uptake of organic anion transporter 4 (OAT4) and organic anion transporting polypeptide 2B1 (OATP2B1) in human placenta. J Steroid Biochem Mol Biol. 2008;111:1–6.

    Article  CAS  PubMed  Google Scholar 

  64. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, et al. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002;300:918–24.

    Article  CAS  PubMed  Google Scholar 

  65. Sata R, Ohtani H, Tsujimoto M, Murakami H, Koyabu N, Nakamura T, et al. Functional analysis of organic cation transporter 3 expressed in human placenta. J Pharmacol Exp Ther. 2005;315:888–95.

    Article  CAS  PubMed  Google Scholar 

  66. Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther. 2004;308:2–9.

    Article  CAS  PubMed  Google Scholar 

  67. Wessler I, Roth E, Deutsch C, Brockerhoff P, Bittinger F, Kirkpatrick CJ, et al. Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters. Br J Pharmacol. 2001;134:951–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kovo M, Kogman N, Ovadia O, Nakash I, Golan A, Hoffman A. Carrier-mediated transport of metformin across the human placenta determined by using the ex vivo perfusion of the placental cotyledon model. Prenat Diagn. 2008;28:544–8.

    Article  CAS  PubMed  Google Scholar 

  69. Tertti K, Ekblad U, Heikkinen T, Rahi M, Rönnemaa T, Laine K. The role of organic cation transporters (OCTs) in the transfer of metformin in the dually perfused human placenta. Eur J Pharm Sci. 2010;39:76–81.

    Article  CAS  PubMed  Google Scholar 

  70. Shekhawat PS, Yang HS, Bennett MJ, Carter AL, Matern D, Tamai I, et al. Carnitine content and expression of mitochondrial beta-oxidation enzymes in placentas of wild-type (OCTN2(+/+)) and OCTN2 Null (OCTN2(−/−)) Mice. Pediatr Res. 2004;56:323–8.

    Article  CAS  PubMed  Google Scholar 

  71. Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, Shimane M, et al. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999;289:768–73.

    CAS  PubMed  Google Scholar 

  72. Errasti-Murugarren E, Diaz P, Godoy V, Riquelme G, Pastor-Anglada M. Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast. Mol Pharmacol. 2011;80:809–17.

    Article  CAS  PubMed  Google Scholar 

  73. Govindarajan R, Bakken AH, Hudkins KL, Lai Y, Casado FJ, Pastor-Anglada M, et al. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1809–22.

    Article  CAS  PubMed  Google Scholar 

  74. Griffiths M, Beaumont N, Yao SY, Sundaram M, Boumah CE, Davies A, et al. Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med. 1997;3:89–93.

    Article  CAS  PubMed  Google Scholar 

  75. Endres CJ, Moss AM, Ishida K, Govindarajan R, Unadkat JD. The role of the equilibrative nucleoside transporter 1 on tissue and fetal distribution of ribavirin in the mouse. Biopharm Drug Dispos. 2016;37:336–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bzoskie L, Yen J, Tseng YT, Blount L, Kashiwai K, Padbury JF. Human placental norepinephrine transporter mRNA: expression and correlation with fetal condition at birth. Placenta. 1997;18:205–10.

    Article  CAS  PubMed  Google Scholar 

  77. Prasad PD, Hoffmans BJ, Moe AJ, Smith CH, Leibach FH, Ganapathy V. Functional expression of the plasma membrane serotonin transporter but not the vesicular monoamine transporter in human placental trophoblasts and choriocarcinoma cells. Placenta. 1996;17:201–7.

    Article  CAS  PubMed  Google Scholar 

  78. Ganapathy V. Drugs of abuse and human placenta. Life Sci. 2011;88:926–30.

    Article  CAS  PubMed  Google Scholar 

  79. Madras BK, Miller GM, Fischman AJ. The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1397–409.

    Article  CAS  PubMed  Google Scholar 

  80. Velasquez JC, Goeden N, Bonnin A. Placental serotonin: implications for the developmental effects of SSRIs and maternal depression. Front Cell Neurosci. 2013;7:47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Schneider H, Miller RK. Receptor-mediated uptake and transport of macromolecules in the human placenta. Int J Dev Biol. 2010;54:367–75.

    Article  CAS  PubMed  Google Scholar 

  82. Akour AA, Kennedy MJ, Gerk P. Receptor-mediated endocytosis across human placenta: emphasis on megalin. Mol Pharm. 2013;10:1269–78.

    Article  CAS  PubMed  Google Scholar 

  83. Arora K, Sequeira JM, Quadros EV. Maternofetal transport of vitamin B12: role of TCblR/CD320 and megalin. FASEB J. 2017;31:3098–106.

    Article  CAS  PubMed  Google Scholar 

  84. Akour AA, Kennedy MJ, Gerk PM. The role of megalin in the transport of gentamicin across BeWo cells, an in vitro model of the human placenta. AAPS J. 2015;17:1193–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Maberry MC, Trimmer KJ, Bawdon RE, Sobhi S, Dax JB, Gilstrap LC 3rd. Antibiotic concentration in maternal blood, cord blood and placental tissue in women with chorioamnionitis. Gynecol Obstet Investig. 1992;33:185–6.

    Article  CAS  Google Scholar 

  86. Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37.

    Article  CAS  PubMed  Google Scholar 

  87. Beck A, Wurch T, Bailly C, Corvaia N. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol. 2010;10:345–52.

    Article  CAS  PubMed  Google Scholar 

  88. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. Am J Gastroenterol. 2009;104:228–33.

    Article  CAS  PubMed  Google Scholar 

  89. Mahadevan U, McConnell RA, Chambers CD. Drug safety and risk of adverse outcomes for pregnant patients with inflammatory bowel disease. Gastroenterology. 2017;152:451–62.e2.

    Article  PubMed  Google Scholar 

  90. Mahadevan U, Wolf DC, Dubinsky M, Cortot A, Lee SD, Siegel CA, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:286–e24.

    Article  CAS  PubMed  Google Scholar 

  91. Malek A. Ex vivo human placenta models: transport of immunoglobulin G and its subclasses. Vaccine. 2003;21:3362–4.

    Article  CAS  PubMed  Google Scholar 

  92. Julsgaard M, Christensen LA, Gibson PR, Gearry RB, Fallingborg J, Hvas CL, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology. 2016;151:110–9.

    Article  CAS  PubMed  Google Scholar 

  93. Porter C, Armstrong-Fisher S, Kopotsha T, Smith B, Baker T, Kevorkian L, et al. Certolizumab pegol does not bind the neonatal Fc receptor (FcRn): Consequences for FcRn-mediated in vitro transcytosis and ex vivo human placental transfer. J Reprod Immunol. 2016;116:7–12.

    Article  CAS  PubMed  Google Scholar 

  94. Miller RK, Mace K, Polliotti B, DeRita R, Hall W, Treacy G. Marginal transfer of ReoPro (Abciximab) compared with immunoglobulin G (F105), inulin and water in the perfused human placenta in vitro. Placenta. 2003;24:727–38.

    Article  CAS  PubMed  Google Scholar 

  95. Kathpalia P, Kane S, Mahadevan U. Detectable drug levels in infants exposed to biologics: so what? Gastroenterology. 2016;151:25–6.

    Article  PubMed  Google Scholar 

  96. Keelan JA, Leong JW, Ho D, Iyer KS. Therapeutic and safety considerations of nanoparticle-mediated drug delivery in pregnancy. Nanomedicine (Lond). 2015;10:2229–47.

    Article  CAS  Google Scholar 

  97. Ockleford CD, Menon G. Differentiated regions of human placental cell surface associated with exchange of materials between maternal and foetal blood: a new organelle and the binding of iron. J Cell Sci. 1977;25:279–91.

    CAS  PubMed  Google Scholar 

  98. Wiu AE. In transport at the cellular level. Symp Soc Exp Biol. 1974;28:521–46.

    Google Scholar 

  99. Wood GW. Mononuclear phagocytes in the human placenta. Placenta. 1980;1:113–23.

    Article  CAS  PubMed  Google Scholar 

  100. Menjoge AR, Rinderknecht AL, Navath RS, Faridnia M, Kim CJ, Romero R, et al. Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy. J Control Release. 2011;150:326–38.

    Article  CAS  PubMed  Google Scholar 

  101. Tian X, Zhu M, Du L, Wang J, Fan Z, Liu J, et al. Intrauterine inflammation increases materno-fetal transfer of gold nanoparticles in a size-dependent manner in murine pregnancy. Small. 2013;9:2432–9.

    Article  CAS  PubMed  Google Scholar 

  102. Tuzel-Kox SN, Patel HM, Kox WJ. Uptake of drug-carrier liposomes by placenta: transplacental delivery of drugs and nutrients. J Pharmacol Exp Ther. 1995;274:104–9.

    CAS  PubMed  Google Scholar 

  103. Bajoria R, Sooranna SR, Contractor SF. Endocytotic uptake of small unilamellar liposomes by human trophoblast cells in culture. Hum Reprod. 1997;12:1343–8.

    Article  CAS  PubMed  Google Scholar 

  104. Bajoria R, Fisk NM, Contractor SF. Liposomal thyroxine: a noninvasive model for transplacental fetal therapy. J Clin Endocrinol Metab. 1997;82:3271–7.

    CAS  PubMed  Google Scholar 

  105. Wick P, Malek A, Manser P, Meili D, Maeder-Althaus X, Diener L, et al. Barrier capacity of human placenta for nanosized materials. Environ Health Perspect. 2010;118:432–6.

    Article  CAS  PubMed  Google Scholar 

  106. Poulsen MS, Mose T, Maroun LL, Mathiesen L, Knudsen LE, Rytting E. Kinetics of silica nanoparticles in the human placenta. Nanotoxicology. 2015;(Suppl 1):79–86.

  107. Myllynen P, Immonen E, Kummu M, Vähäkangas K. Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues. Expert Opin Drug Metab Toxicol. 2009;5:1483–99.

    Article  CAS  PubMed  Google Scholar 

  108. Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human placenta. Clin Pharmacokinet. 2004;43:487–514.

    Article  CAS  PubMed  Google Scholar 

  109. Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi. 2003;123:369–75.

    Article  CAS  PubMed  Google Scholar 

  110. Pavek P, Smutny T. Nuclear receptors in regulation of biotransformation enzymes and drug transporters in the placental barrier. Drug Metab Rev. 2014;46:19–32.

    Article  CAS  PubMed  Google Scholar 

  111. Collier AC, Ganley NA, Tingle MD, Blumenstein M, Marvin KW, Paxton JW, et al. UDP-glucuronosyltransferase activity, expression and cellular localization in human placenta at term. Biochem Pharmacol. 2002;63:409–19.

    Article  CAS  PubMed  Google Scholar 

  112. Corbel T, Perdu E, Gayrard V, Puel S, Lacroix MZ, Viguie C, et al. Conjugation and deconjugation reactions within the fetoplacental compartment in a sheep model: a key factor determining bisphenol A fetal exposure. Drug Metab Dispos. 2015;43:467–76.

    Article  CAS  PubMed  Google Scholar 

  113. Schuetz JD, Kauma S, Guzelian PS. Identification of the fetal liver cytochrome CYP3A7 in human endometrium and placenta. J Clin Invest. 1993;92:1018–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shuster DL, Bammler TK, Beyer RP, Macdonald JW, Tsai JM, Farin FM, et al. Gestational age-dependent changes in gene expression of metabolic enzymes and transporters in pregnant mice. Drug Metab Dispos. 2013;41:332–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Liebes L, Mendoza S, Lee JD, Dancis J. Further observations on zidovudine transfer and metabolism by human placenta. AIDS. 1993;7:590–2.

    Article  CAS  PubMed  Google Scholar 

  116. Dancis J, Lee JD, Mendoza S, Liebes L. Transfer and metabolism of dideoxyinosine by the perfused human placenta. J Acquir Immune Defic Syndr. 1993;6:2–6.

    CAS  PubMed  Google Scholar 

  117. Pienimäki P, Lampela E, Hakkola J, Arvela P, Raunio H, Vähäkangas K. Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta. Epilepsia. 1997;38:309–16.

    Article  PubMed  Google Scholar 

  118. Myllynen P, Pienimäki P, Raunio H, Vähäkangas K. Microsomal metabolism of carbamazepine and oxcarbazepine in liver and placenta. Hum Exp Toxicol. 1998;17:668–76.

    Article  CAS  PubMed  Google Scholar 

  119. Zharikova OL, Fokina VM, Nanovskaya TN, Hill RA, Mattison DR, Hankins GD, et al. Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. Biochem Pharmacol. 2009;78:1483–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Deshmukh SV, Nanovskaya TN, Ahmed MS. Aromatase is the major enzyme metabolizing buprenorphine in human placenta. J Pharmacol Exp Ther. 2003;306:1099–105.

    Article  CAS  PubMed  Google Scholar 

  121. Nanovskaya TN, Deshmukh SV, Nekhayeva IA, Zharikova OL, Hankins GD, Ahmed MS. Methadone metabolism by human placenta. Biochem Pharmacol. 2004;68:583–91.

    Article  CAS  PubMed  Google Scholar 

  122. Schenker S, Yang Y, Mattiuz E, Tatum D, Lee M. Olanzapine transfer by human placenta. Clin Exp Pharmacol Physiol. 1999;26:691–7.

    Article  CAS  PubMed  Google Scholar 

  123. Collier AC, Keelan JA, Van Zijl PE, Paxton JW, Mitchell MD, Tingle MD. Human placental glucuronidation and transport of 3'azido-3′-deoxythymidine and uridine diphosphate glucuronic acid. Drug Metab Dispos. 2004;32:813–20.

    Article  CAS  PubMed  Google Scholar 

  124. Pasanen M, Pelkonen O. The expression and environmental regulation of P450 enzymes in human placenta. Crit Rev Toxicol. 1994;24:211–29.

    Article  CAS  PubMed  Google Scholar 

  125. Stejskalova L, Vecerova L, Perez LM, Vrzal R, Dvorak Z, Nachtigal P, et al. Aryl hydrocarbon receptor and aryl hydrocarbon nuclear translocator expression in human and rat placentas and transcription activity in human trophoblast cultures. Toxicol Sci. 2011;123:26–36.

    Article  CAS  PubMed  Google Scholar 

  126. Levy G. Pharmacokinetics of fetal and neonatal exposure to drugs. Obstet Gynecol. 1981;58(5 Suppl):9s–16s.

    CAS  PubMed  Google Scholar 

  127. Tomson G, Garle RI, Thalme B, Nisell H, Nylund L, Rane A. Maternal kinetics and transplacental passage of pethidine during labour. Br J Clin Pharmacol. 1982;13:653–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Rubinchik-Stern M, Shmuel M, Bar J, Eyal S, Kovo M. Maternal-fetal transfer of indocyanine green across the perfused human placenta. Reprod Toxicol. 2016;62:100–5.

    Article  CAS  PubMed  Google Scholar 

  129. Cool DR, Liebach FH, Ganapathy V. Interaction of fluoxetine with the human placental serotonin transporter. Biochem Pharmacol. 1990;40:2161–7.

    Article  CAS  PubMed  Google Scholar 

  130. Jayanthi LD, Vargas G, DeFelice LJ. Characterization of cocaine and antidepressant-sensitive norepinephrine transporters in rat placental trophoblasts. Br J Pharmacol. 2002;135:1927–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lahjouji K, Elimrani I, Lafond J, Leduc L, Qureshi IA, Mitchell GA. L-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2. Am J Physiol Cell Physiol. 2004;287:C263–9.

    Article  CAS  PubMed  Google Scholar 

  132. Wu SP, Shyu MK, Liou HH, Gau CS, Lin CJ. Interaction between anticonvulsants and human placental carnitine transporter. Epilepsia. 2004;45:204–10.

    Article  CAS  PubMed  Google Scholar 

  133. Hirano T, Yasuda S, Osaka Y, Asari M, Kobayashi M, Itagaki S, et al. The inhibitory effects of fluoroquinolones on L-carnitine transport in placental cell line BeWo. Int J Pharm. 2008;351:113–8.

    Article  CAS  PubMed  Google Scholar 

  134. Fathe K, Palacios A, Finnell RH. Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol. 2014;100:592–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Keating E, Goncalves P, Campos I, Costa F, Martel F. Folic acid uptake by the human syncytiotrophoblast: interference by pharmacotherapy, drugs of abuse and pathological conditions. Reprod Toxicol. 2009;28:511–20.

    Article  CAS  PubMed  Google Scholar 

  136. Acevedo CG, Rojas S, Bravo I. L-arginine transport at the fetal side of human placenta: effect of aspirin in pregnancy. Exp Physiol. 1999;84:1127–36.

    Article  CAS  PubMed  Google Scholar 

  137. Williams JB, Mallorga PJ, Conn PJ, Pettibone DJ, Sur C. Effects of typical and atypical antipsychotics on human glycine transporters. Schizophr Res. 2004;71:103–12.

    Article  PubMed  Google Scholar 

  138. He B, Zhang N, Zhao R. Dexamethasone downregulates SLC7A5 expression and promotes cell cycle arrest, autophagy and apoptosis in BeWo cells. J Cell Physiol. 2016;231:233–42.

    Article  CAS  PubMed  Google Scholar 

  139. Kingdom JC, Drewlo S. Is heparin a placental anticoagulant in high-risk pregnancies? Blood. 2011;118:4780–8.

    Article  CAS  PubMed  Google Scholar 

  140. Schwarz EB, Maselli J, Norton M, Gonzales R. Prescription of teratogenic medications in United States ambulatory practices. Am J Med. 2005;118:1240–9.

    Article  PubMed  Google Scholar 

  141. Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol. 2012;11:803–13.

    Article  CAS  PubMed  Google Scholar 

  142. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study. Neurology. 2015;85:866–72.

    Article  CAS  PubMed  Google Scholar 

  143. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10:609–17.

    Article  CAS  PubMed  Google Scholar 

  144. Meador KJ, Baker GA, Browning N, Clayton-Smith J, Combs-Cantrell DT, Cohen M, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360:1597–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12:244–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309:1696–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wood AG, Nadebaum C, Anderson V, Reutens D, Barton S, O'Brien TJ, et al. Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy. Epilepsia. 2015;56:1047–55.

    Article  CAS  PubMed  Google Scholar 

  148. Cohen MJ, Meador KJ, Browning N, May R, Baker GA, Clayton-Smith J, et al. Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years. Epilepsy Behav. 2013;29:308–15.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Nakamura H, Ushigome F, Koyabu N, Satoh S, Tsukimori K, Nakano H, et al. Proton gradient-dependent transport of valproic acid in human placental brush-border membrane vesicles. Pharm Res. 2002;19:154–61.

    Article  CAS  PubMed  Google Scholar 

  150. Utoguchi N, Audus KL. Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line. Int J Pharm. 2000;195:115–24.

    Article  CAS  PubMed  Google Scholar 

  151. Furugen A, Ishiguro Y, Kobayashi M, Narumi K, Nishimura A, Hirano T, et al. Involvement of l-type amino acid transporter 1 in the transport of gabapentin into human placental choriocarcinoma cells. Reprod Toxicol. 2017;67:48–55.

    Article  CAS  PubMed  Google Scholar 

  152. Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: Does a fetal accumulation occur during pregnancy? Epilepsia. 2005;46:1621–4.

    Article  PubMed  Google Scholar 

  153. Rubinchik-Stern M, Shmuel M, Eyal S. Antiepileptic drugs alter the expression of placental carriers: an in vitro study in a human placental cell line. Epilepsia. 2015;56:1023–32.

    Article  CAS  PubMed  Google Scholar 

  154. Meir M, Bishara A, Mann A, Udi S, Portnoy E, Shmuel M, et al. Effects of valproic acid on the placental barrier in the pregnant mouse: optical imaging and transporter expression studies. Epilepsia. 2016;57:e108–12.

    Article  CAS  PubMed  Google Scholar 

  155. Ohashi R, Tamai I, Yabuuchi H, Nezu JI, Oku A, Sai Y, et al. Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999;291:778–84.

    CAS  PubMed  Google Scholar 

  156. Asadi-Pooya AA, Mintzer S, Sperling MR. Nutritional supplements, foods, and epilepsy: is there a relationship? Epilepsia. 2008;49:1819–27.

    Article  CAS  PubMed  Google Scholar 

  157. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:Cd004454.

    PubMed  Google Scholar 

  158. Walker N, Filis P, Soffientini U, Bellingham M, O'Shaughnessy PJ, Fowler PA. Placental transporter localization and expression in the human: the importance of species, sex, and gestational age differencesdagger. Biol Reprod. 2017;96:733–42.

    Article  PubMed  PubMed Central  Google Scholar 

  159. Kalabis GM, Petropoulos S, Gibb W, Matthews SG. Multidrug resistance phosphoglycoprotein (ABCB1) expression in the guinea pig placenta: developmental changes and regulation by betamethasone. Can J Physiol Pharmacol. 2009;87:973–8.

    Article  CAS  PubMed  Google Scholar 

  160. Petropoulos S, Gibb W, Matthews SG. Effect of glucocorticoids on regulation of placental multidrug resistance phosphoglycoprotein (P-gp) in the mouse. Placenta. 2010;31:803–10.

    Article  CAS  PubMed  Google Scholar 

  161. Salje K, Lederer K, Oswald S, Dazert E, Warzok R, Siegmund W. Effects of rifampicin, dexamethasone, St. John’s Wort and thyroxine on maternal and foetal expression of Abcb1 and organ distribution of talinolol in pregnant rats. Basic Clin Pharmacol Toxicol. 2012;111:99–105.

    CAS  PubMed  Google Scholar 

  162. Manceau S, Giraud C, Decleves X, Scherrmann JM, Artiguebieille F, Goffinet F, et al. ABC drug transporter and nuclear receptor expression in human cytotrophoblasts: influence of spontaneous syncytialization and induction by glucocorticoids. Placenta. 2012;33:927–32.

    Article  CAS  PubMed  Google Scholar 

  163. Hodyl NA, Stark MJ, Butler M, Clifton VL. Placental P-glycoprotein is unaffected by timing of antenatal glucocorticoid therapy but reduced in SGA preterm infants. Placenta. 2013;34:325–30.

    Article  CAS  PubMed  Google Scholar 

  164. Petropoulos S, Gibb W, Matthews SG. Glucocorticoid regulation of placental breast cancer resistance protein (Bcrp1) in the mouse. Reprod Sci. 2011;18:631–9.

    Article  CAS  PubMed  Google Scholar 

  165. Paakki P, Kirkinen P, Helin H, Pelkonen O, Raunio H, Pasanen M. Antepartum glucocorticoid therapy suppresses human placental xenobiotic and steroid metabolizing enzymes. Placenta. 2000;21:241–6.

    Article  CAS  PubMed  Google Scholar 

  166. Audette MC, Challis JR, Jones RL, Sibley CP, Matthews SG. Synthetic glucocorticoid reduces human placental system a transport in women treated with antenatal therapy. J Clin Endocrinol Metab. 2014;99:E2226–33.

    Article  CAS  PubMed  Google Scholar 

  167. Günthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the international antiviral society–USA panel. JAMA. 2016;316:191–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. McCormack SA, Best BM. Protecting the fetus against HIV infection: a systematic review of placental transfer of antiretrovirals. Clin Pharmacokinet. 2014;53:989–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Beghin D, Forestier F, Noel-Hudson MS, Gavard L, Guibourdenche J, Farinotti R, et al. Modulation of endocrine and transport functions in human trophoblasts by saquinavir and nelfinavir. Eur J Obstet Gynecol Reprod Biol. 2010;152:55–9.

    Article  CAS  PubMed  Google Scholar 

  170. Camus M, Deloménie C, Didier N, Faye A, Gil S, Dauge MC, et al. Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women. Placenta. 2006;27:699–706.

    Article  CAS  PubMed  Google Scholar 

  171. Zoeller BB. Treatment of fetal supraventricular tachycardia. Curr Treat Options Cardiovasc Med. 2017;19:7.

    Article  PubMed  Google Scholar 

  172. Ilekis JV, Tsilou E, Fisher S, Abrahams VM, Soares MJ, Cross JC, et al. Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Am J Obstet Gynecol. 2016;215(1 Suppl):S1–s46.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Tomson T, Marson A, Boon P, Canevini MP, Covanis A, Gaily E, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56:1006–19.

    Article  CAS  PubMed  Google Scholar 

  174. Fowler DW, Eadie MJ, Dickinson RG. Transplacental transfer and biotransformation studies of valproic acid and its glucuronide(s) in the perfused human placenta. J Pharmacol Exp Ther. 1989;249:318–23.

    CAS  PubMed  Google Scholar 

  175. Nau H. Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol. 1985;80:243–50.

    Article  CAS  PubMed  Google Scholar 

  176. Eskandari S, Varshosaz J, Minaiyan M, Tabbakhian M. Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model. Int J Nanomedicine. 2011;6:363–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Bishara A, Meir M, Portnoy E, Shmuel M, Eyal S. Near infrared imaging of indocyanine green distribution in pregnant mice and effects of concomitant medications. Mol Pharm. 2015;12:3351–7.

    Article  CAS  PubMed  Google Scholar 

  178. Kaitu'u-Lino TJ, Pattison S, Ye L, Tuohey L, Sluka P, MacDiarmid J, et al. Targeted nanoparticle delivery of doxorubicin into placental tissues to treat ectopic pregnancies. Endocrinology. 2013;154:911–9.

    Article  PubMed  CAS  Google Scholar 

  179. Blundell C, Tess ER, Schanzer ASR, Coutifaris C, Su EJ, Parry S, et al. A microphysiological model of the human placental barrier. Lab Chip. 2016;16:3065–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge the support of the Israel Science Foundation (ISF) Grant 506/13.

Sara Eyal is affiliated with the David R. Bloom Centre for Pharmacy and Dr. Adolf and Klara Brettler Centre for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.

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  1. Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Ein Kerem, 91120, Jerusalem, Israel

    Nino Tetro, Sonia Moushaev, Miriam Rubinchik-Stern & Sara Eyal

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  1. Nino Tetro
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  2. Sonia Moushaev
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Guest Editor: Sara Eyal

Dedicated to (late) Dr. Zvi Ben Zvi, Ben Gurion University of the Negev, Beer Sheva, Israel, for his contribution to the field of maternal-fetal pharmacology.

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Tetro, N., Moushaev, S., Rubinchik-Stern, M. et al. The Placental Barrier: the Gate and the Fate in Drug Distribution. Pharm Res 35, 71 (2018). https://doi.org/10.1007/s11095-017-2286-0

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