Clinical Pharmacokinetics

, Volume 43, Issue 8, pp 487–514 | Cite as

Drug Transfer and Metabolism by the Human Placenta

  • Michael R. Syme
  • James W. Paxton
  • Jeffrey A. KeelanEmail author
Review Article


The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood.

However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations.

The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification.

The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.


Digoxin Buprenorphine Saquinavir Human Placenta Maternal Blood 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Financial assistance was received from the Maurice and Phyllis Paykel Trust and Uniservices Limited. There are no conflicts of interest directly relevant to the content of this review.


  1. 1.
    Smith CH, Moe AJ, Ganapathy V. Nutrient transport pathways across the epithelium of the placenta. Annu Rev Nutr 1992; 12: 183–206PubMedCrossRefGoogle Scholar
  2. 2.
    Hahn T, Desoye G. Ontogeny of glucose transport systems in the placenta and its progenitor tissues. Early Pregnancy 1996; 2: 168–82PubMedGoogle Scholar
  3. 3.
    Moe AJ. Placental amino acid transport. Am J Physiol 1995; 268: C1321–31PubMedGoogle Scholar
  4. 4.
    Seeds AE. Placental transfer. In: Barnes AC, editor. Intrauterine development. Philadelphia: Lea & Febiger, 1968: 103–28Google Scholar
  5. 5.
    Hill MD, Abramson FP. The significance of plasma protein binding on the fetal/maternal distribution of drugs at steadystate. Clin Pharmacokinet 1988; 14: 156–70PubMedCrossRefGoogle Scholar
  6. 6.
    Meigs RA, Ryan KJ. Cytochrome P-450 and steroid biosynthesis in the human placenta. Biochim Biophys Acta 1968; 165: 476–82CrossRefGoogle Scholar
  7. 7.
    Collier AC, Ganley NA, Tingle MD, et al. UDP-glucuronosyltransferase activity, expression and cellular localization in human placenta at term. Biochem Pharmacol 2002; 63: 409–19PubMedCrossRefGoogle Scholar
  8. 8.
    Pacifici GM, Rane A. Glutathione S-transferase in the human placenta at different stages in pregnancy. Drug Metab Dispos 1981; 9: 472–5PubMedGoogle Scholar
  9. 9.
    Pacifici GM, Rane A. Epoxide hydroxylase in human placenta at different stages in pregnancy. Dev Pharmacol Ther 1983; 6: 83–93PubMedGoogle Scholar
  10. 10.
    Pasanen M. The expression and regulation of drug metabolism in human placenta. Adv Drug Deliv Rev 1999; 38: 81–97PubMedCrossRefGoogle Scholar
  11. 11.
    van der Aa EM, Peereboom-Stegeman JHJC, Noordhoek J, et al. Mechanisms of drug transfer across the placenta. Pharm World Sci 1998; 20: 139–48PubMedCrossRefGoogle Scholar
  12. 12.
    Kaufmann P, Scheffen I. Placental development. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology. Philadelphia: WB Saunders, 1992: 47–56Google Scholar
  13. 13.
    Moore KL, Persaud TVN. Before we are born: essentials of embryology and birth defects, 5th edition. Philadelphia: W.B. Saunders Company, 1998Google Scholar
  14. 14.
    Enders AC, Blankenship TN. Comparative placental structure. Adv Drug Deliv Rev 1999; 38: 3–16PubMedCrossRefGoogle Scholar
  15. 15.
    Ferm VH. The rapid detection of teratogenic activity. Lab Invest 1965; 14: 1500–5PubMedGoogle Scholar
  16. 16.
    King CT, Howell J. Teratogenic effect of buclizine and hydroxyzine in the rat and chlorcyclizine in the mouse. Am J Obstet Gynecol 1966; 95: 109–11PubMedGoogle Scholar
  17. 17.
    Fabro S, Smith RL. The teratogenic activity of thalidomide in the rabbit. J Pathol Bacteriol 1966; 91: 511–9PubMedCrossRefGoogle Scholar
  18. 18.
    Rodin AE, Koller LA, Taylar JD. Association of thalidomide (Kevadon) with congenital anomalies. CMAJ 1962; 86: 744–6Google Scholar
  19. 19.
    Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet 1995; 28(3): 235–69PubMedCrossRefGoogle Scholar
  20. 20.
    Garland M. Pharmacology of drug transfer across the placenta. Obstet Gynecol Clin North Am 1998; 25: 21–42PubMedCrossRefGoogle Scholar
  21. 21.
    Nau H. Physicochemical and structural properties regulating placental drug transfer. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology. Philadelphia: WB Saunders, 1992: 130–41Google Scholar
  22. 22.
    Ward RM. Drug therapy of the fetus. J Clin Pharmacol 1993; 33: 780–9PubMedGoogle Scholar
  23. 23.
    Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res 1984; 34: 557–60PubMedCrossRefGoogle Scholar
  24. 24.
    Forestier F, Daffos F, Rainaut M, et al. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy [letter]. Thromb Haemost 1987; 57: 234PubMedGoogle Scholar
  25. 25.
    Omri A, Delaloye JF, Andersen H, et al. Low molecular weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy. Thromb Haemost 1989; 61: 55–6PubMedGoogle Scholar
  26. 26.
    Schneider D, Heilmann L, Harenberg J. Placental transfer of low-molecular weight heparin. Geburtshilfe Frauenheilkd 1995; 55: 93–8PubMedCrossRefGoogle Scholar
  27. 27.
    Dickinson RG, Fowler DW, Kluck RM. Maternofetal transfer of phenytoin, p-hydroxy-phenytoin and p-hydroxy-phenytoinglucuronide in the perfused human placenta. Clin Exp Pharmacol Physiol 1989; 16: 789–97PubMedCrossRefGoogle Scholar
  28. 28.
    Paxton JW. α1-Acid glycoprotein and binding of basic drugs. Methods Find Exp Clin Pharmacol 1983; 5: 635–48PubMedGoogle Scholar
  29. 29.
    Kragh-Hansen U. Molecular aspects of ligand binding to serum albumin. Pharmacol Rev 1981; 33: 17–53PubMedGoogle Scholar
  30. 30.
    Wood M, Wood AJJ. Changes in plasma drug binding and α1-acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 1981; 29: 522–6PubMedCrossRefGoogle Scholar
  31. 31.
    Thomas J, Long G, Morgan D. Plasma protein binding and placental transfer of bupivacaine. Clin Pharmacol Ther 1976; 19: 426–34PubMedGoogle Scholar
  32. 32.
    Herngren L, Ehrnebo M, Boréus LO. Drug binding to plasma proteins during human pregnancy and in the perinatal period: studies in cloxacillin and alprenolol. Dev Pharmacol Ther 1983; 6: 110–44PubMedGoogle Scholar
  33. 33.
    Krauer B, Dayer P, Anner R. Changes in serum albumin and alpha-1-acid glycoprotein concentrations during pregnancy: an analysis of fetal-maternal pairs. Br J Obstet Gynaecol 1984; 91: 875–81PubMedCrossRefGoogle Scholar
  34. 34.
    Hamar C, Levy G. Serum protein binding of drugs and bilirubin in newborn infants and their mothers. Clin Pharmacol Ther 1980; 28: 58–63PubMedCrossRefGoogle Scholar
  35. 35.
    Herman NL, Li AT, Van Decar TK, et al. Transfer of methohexital across the perfused human placenta. J Clin Anesth 2000; 12: 25–30PubMedCrossRefGoogle Scholar
  36. 36.
    Schmolling J, Jung S, Reinsberg J, et al. Digoxin transfer across the isolated placenta is influenced by maternal and fetal albumin concentrations. Reprod Fertil Dev 1996; 8: 969–74PubMedCrossRefGoogle Scholar
  37. 37.
    Tsadkin M, Holcberg G, Sapir O, et al. Albumin-dependent digoxin transfer in isolated perfused human placenta. Int J Clin Pharmacol Ther 2001; 39: 158–61PubMedGoogle Scholar
  38. 38.
    Wallace S. Altered plasma albumin in the newborn infant. Br J Clin Pharmacol 1977; 14: 82–5CrossRefGoogle Scholar
  39. 39.
    Krasner J, Giacoia GP, Yaffe SJ. Drug protein binding in the newborn infant. Ann N Y Acad Sci 1973; 226: 101–14PubMedCrossRefGoogle Scholar
  40. 40.
    Reynolds F. Transfer of drugs. In: Chamberlain GVP, Wilkinson AW, editors. Placental transfer. Kent: Pitman Medical Publishing, 1979: 166–81Google Scholar
  41. 41.
    Nau H, Luck W, Kuhnz W. Decreased serum protein binding of diazepam and its major metabolite in the neonate during the first postnatal week relate to increased free fatty acid levels. Br J Clin Pharmacol 1984; 17: 92–8PubMedCrossRefGoogle Scholar
  42. 42.
    Ridd MJ, Brown KF, Nation RL, et al. Differential transplacental binding of diazepam: causes and implications. Eur J Clin Pharmacol 1983; 24: 595–601PubMedCrossRefGoogle Scholar
  43. 43.
    Sastry BVR. Techniques to study human placental transport. Adv Drug Deliv Rev 1999; 38: 17–39PubMedCrossRefGoogle Scholar
  44. 44.
    Ala-Kokko TI, Myllynen P, Vähäkangas K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int J Obstet Anesth 2000; 9: 26–38CrossRefGoogle Scholar
  45. 45.
    Nanovskaya T, Deshmukh S, Brooks M, et al. Transplacental transfer and metabolism of buprenorphine. J Pharmacol Exp Ther 2002; 300: 26–33PubMedCrossRefGoogle Scholar
  46. 46.
    Ala-Kokko TI, Pienimaki P, Herva R, et al. Transfer of lidocaine and bupivacaine across the isolated perfused human placenta. Pharmacol Toxicol 1995; 77: 142–8PubMedCrossRefGoogle Scholar
  47. 47.
    Dancis J, Jansen V, Levitz M. Placental transfer of steroids: effect of binding to serum albumin and to placenta. Am J Physiol 1980; 238: E208–13PubMedGoogle Scholar
  48. 48.
    Aherne W, Dunnill MS. Quantitative aspects of placental structure. J Pathol Bacteriol 1966; 91: 123–39PubMedCrossRefGoogle Scholar
  49. 49.
    de Sweet M. Embryology. In: de Sweit M, Chamberlain G, editors. Basic science of obstetrics and gynecology. Edinburgh: Churchill Livingstone, 1992: 27–52Google Scholar
  50. 50.
    Aherne W, Dunnill MS. Morphometry of the human placenta. Br Med Bull 1966; 22: 5–8PubMedGoogle Scholar
  51. 51.
    Reynolds F, Knott C. Pharmacokinetics in pregnancy and placental transfer. Oxf Rev Reprod Biol 1989; 11: 389–449PubMedGoogle Scholar
  52. 52.
    Bourget P, Roulot C, Fernandez H. Models for placental transfer studies of drugs. Clin Pharmacokinet 1995; 28(2): 161–80PubMedCrossRefGoogle Scholar
  53. 53.
    Gembruch U, Hansmann M, Bald R.B. Direct intrauterine fetal treatment of fetal tachyarrhythmia with severe hydrops fetalis by antiarrythmic drugs. Fetal Ther 1988; 3: 210–5PubMedCrossRefGoogle Scholar
  54. 54.
    Schmolling J, Renke K, Richter O, et al. Digoxin, flecainamide, and amiodarone transfer across the placenta and the effects of an elevated umbilical venous pressure on the transfer rate. Ther Drug Monit 2000; 22: 582–8PubMedCrossRefGoogle Scholar
  55. 55.
    Folkart GR, Dancis J, Monye WL. Transfer of carbohydrates across guinea pig placenta. Am J Obstet Gynecol 1960; 80: 221–3PubMedGoogle Scholar
  56. 56.
    Henderson GI, Hu ZQ, Yang Y, et al. Ganciclovir transfer by human placenta and its effects on rat fetal cells. Am J Med Sci 1993; 306: 151–6PubMedCrossRefGoogle Scholar
  57. 57.
    Kudo Y, Urabe T, Fujiwara A, et al. Carrier-mediated transport system for cephalexin in human placental brush-border membrane vesicles. Biochim Biophys Acta 1989; 978: 313–8PubMedCrossRefGoogle Scholar
  58. 58.
    Fant ME, Yeakley J, Harrison RW. Evidence for carrier-mediated transport of glucocorticoids by human placental membrane vesicles. Biochim Biophys Acta 1983; 731: 415–20PubMedCrossRefGoogle Scholar
  59. 59.
    Bissonnette JM. Placental transport of carbohydrates. Mead Johnson Symp Perinat Dev Med 1981; 18: 21–3PubMedGoogle Scholar
  60. 60.
    Ganapathy V, Prasad PD, Ganapathy ME, et al. Placental transporters relevant to drug distribution across the maternalfetal interface. J Pharmacol Exp Ther 2000; 294: 413–20PubMedGoogle Scholar
  61. 61.
    St-Pierre V, Ugele B, Gambling L, et al. Mechanisms of drug transfer across the human placenta: a workshop report. Placenta 2002; 23 Suppl. A: 159–64CrossRefGoogle Scholar
  62. 62.
    Gottesman MM, Hrycyna CA, Schoenlein PV, et al. Genetic analysis of the multidrug transporter. Annu Rev Genet 1995; 29: 607–49PubMedCrossRefGoogle Scholar
  63. 63.
    Gottesman M, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993; 62: 385–427PubMedCrossRefGoogle Scholar
  64. 64.
    Huang L, Hoffman T, Vore M. Adenosine triphosphate-dependent transport of estradiol-17β-D-glucuronide in membrane vesicles by MDR1 expressed in insect cells. Hepatology 1998; 28: 1371–7PubMedCrossRefGoogle Scholar
  65. 65.
    King M, Su W, Chang A, et al. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci 2001; 4: 268–74PubMedCrossRefGoogle Scholar
  66. 66.
    Raggers RJ, Vogels I, van Meer G. Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor. Biochem J 2001; 357: 859–65PubMedCrossRefGoogle Scholar
  67. 67.
    Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101: 289–94PubMedCrossRefGoogle Scholar
  68. 68.
    Hunter J, Jepson MA, Tsuruo T, et al. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators. J Biol Chem 1993; 268: 14991–7PubMedGoogle Scholar
  69. 69.
    Schinkel AH, Wagenaar E, van Deemter L, et al. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698–705PubMedCrossRefGoogle Scholar
  70. 70.
    Cordon-Cardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277–87PubMedCrossRefGoogle Scholar
  71. 71.
    Sugawara I, Kataoka I, Morishita Y, et al. Tissue distribution of p-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res 1988; 48: 1926–9PubMedGoogle Scholar
  72. 72.
    Ushigome F, Takanaga H, Matsuo H, et al. Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein. Eur J Pharmacol 2000; 408: 1–10PubMedCrossRefGoogle Scholar
  73. 73.
    Pávek P, Fendrich Z, Staud F, et al. Influence of p-glycoprotein on the transplacental passage of cyclosporin. J Pharm Sci 2001; 10: 1583–92CrossRefGoogle Scholar
  74. 74.
    Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdr-1-type (drugtransporting) P-glycoproteins. Proc Natl Acad Sci U S A 1997; 94: 4028–33PubMedCrossRefGoogle Scholar
  75. 75.
    Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491–502PubMedCrossRefGoogle Scholar
  76. 76.
    Lankas GR, Wise LD, Cartwright ME, et al. Placental P-glycoprotein deficiency enhance susceptibility to chemically induced birth defects in mice. Reprod Toxicol 1998; 12: 457–63PubMedCrossRefGoogle Scholar
  77. 77.
    Smit JW, Huisman MT, van Tellingen O, et al. Absence or pharmacologcal blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 1999; 104: 1441–7PubMedCrossRefGoogle Scholar
  78. 78.
    König J, Nies AT, Cui Y, et al. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1999; 1461: 377–94PubMedCrossRefGoogle Scholar
  79. 79.
    Borst P, Evers R, Kool M, et al. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000; 92: 1295–302PubMedCrossRefGoogle Scholar
  80. 80.
    Hipfner DR, Deeley RG, Cole SPC. Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta 1999; 1461: 359–76PubMedCrossRefGoogle Scholar
  81. 81.
    Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992; 258: 1650–4PubMedCrossRefGoogle Scholar
  82. 82.
    Kool M, de Haas M, Scheffer GL, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1 ), in human cancer cell lines. Cancer Res 1997; 57: 3537–47PubMedGoogle Scholar
  83. 83.
    Suzuki H, Sugiyama Y. Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin Liver Dis 1998; 18: 359–76PubMedCrossRefGoogle Scholar
  84. 84.
    Gerk PM, Vore M. Regulation and expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J Pharm Exp Ther 2002; 302: 407–15CrossRefGoogle Scholar
  85. 85.
    Sugawara I, Akiyama S, Scheper RJ, et al. Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. Cancer Lett 1997; 112: 23–31PubMedCrossRefGoogle Scholar
  86. 86.
    St-Pierre V, Serrano MA, Macias RIR, et al. Expression of members of the multidrug resistance protein family in human term placenta. Am J Physiol Regul Integr Comp Physiol 2000; 279: R1495–503PubMedGoogle Scholar
  87. 87.
    Flens MJ, Zaman GJR, van der Valk P, et al. Tissue distribution of the multidrug resistance protein. Am J Pathol 1996; 148: 1237–47PubMedGoogle Scholar
  88. 88.
    Cui Y, König J, Buchholz U, et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 1999; 55: 929–37PubMedGoogle Scholar
  89. 89.
    Allikmets R, Schriml LM, Hutchinson A, et al. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 1998; 58: 5337–9PubMedGoogle Scholar
  90. 90.
    Allen JD, Brinkhuis RF, Wijnholds J, et al. The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res 1999; 59: 4237–41PubMedGoogle Scholar
  91. 91.
    Jonker JW, Smit JW, Brinkhuis RF, et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst 2000; 92: 1651–6PubMedCrossRefGoogle Scholar
  92. 92.
    Ramamoorthy S, Leibach FH, Ganapathy V. Partial purification and characterization of the human placental serotonin transporter. Placenta 1993; 14: 449–61PubMedCrossRefGoogle Scholar
  93. 93.
    Ramamoorthy S, Prasad PD, Kulanthaivel P, et al. Expression of a cocaine-sensitive noradrenaline transporter in the human placental syncytiotrophoblast. Biochemistry 1993; 32: 1346–53PubMedCrossRefGoogle Scholar
  94. 94.
    Kekuda R, Prasad PD, Wu X, et al. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 1998; 273: 15971–9PubMedCrossRefGoogle Scholar
  95. 95.
    Ramamoorthy JD, Ramamoorthy S, Leibach FH, et al. Human placental monoamine transporters as targets for amphetamines. Am J Obstet Gynecol 1995; 173: 1782–7PubMedCrossRefGoogle Scholar
  96. 96.
    Shearman LP, Meyer JS. Cocaine up-regulates norepinephrine transporter binding in the rat placenta. Eur J Pharmacol 1999; 386: 1–6PubMedCrossRefGoogle Scholar
  97. 97.
    Kenney SP, Kekuda R, Prasad PD, et al. Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta. Am J Obstet Gynecol 1999; 181: 491–7PubMedCrossRefGoogle Scholar
  98. 98.
    Wu X, Huang W, Prasad PD. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J Pharmacol Exp Ther 1999; 290: 1482–92PubMedGoogle Scholar
  99. 99.
    Ohashi R, Tamai I, Yabuuchi H, et al. Na+-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther 1999; 291: 778–84PubMedGoogle Scholar
  100. 100.
    Wu X, Prasad PD, Leibach FH, et al. cDNA sequence, transport function, and genomic organisation of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun 1998; 246: 589–95PubMedCrossRefGoogle Scholar
  101. 101.
    Wu X, George RL, Huang W, et al. Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta 2000; 1466: 315–27PubMedCrossRefGoogle Scholar
  102. 102.
    Price NT, Jakson VN, Halestrap AP. Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past. Biochem J 1998; 329: 321–8PubMedGoogle Scholar
  103. 103.
    Ganapathy V, Ganapathy ME, Tiruppathi C, et al. Sodium gradient-driven, high-affinity, uphill transport of succinate in human placental brush-border membrane vesicles. Biochem J 1988; 249: 179–84PubMedGoogle Scholar
  104. 104.
    Balkovetz DF, Leibach FH, Mahesh VB, et al. A proton gradient is the driving force for the uphill transport of lactate in human placental brush-border membrane vescicles. J Biol Chem 1988; 263: 13823–30PubMedGoogle Scholar
  105. 105.
    Poole RC, Halestrap AP. Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 1993; 264: C761–82PubMedGoogle Scholar
  106. 106.
    Malone FD, D’Alton ME. Drugs in pregnancy: anticonvulsants. Semin Perinatol 1997; 21: 114–23PubMedCrossRefGoogle Scholar
  107. 107.
    Ishizaki T, Yokochi K, Chiba K, et al. Placental transfer of anticonvulsants (phenobarbital, phenytoin, valproic acid) and the elimination from neonates. Pediatr Pharmacol 1981; 1: 291–303Google Scholar
  108. 108.
    Utoguchi N, Audus KL. Carrier-mediated transport of valproic acid in BeWo cells, a human trophoblast cell line. Int J Pharm 2000; 195: 115–24PubMedCrossRefGoogle Scholar
  109. 109.
    Ushigome F, Takanaga H, Matsuo H, et al. Uptake mechanism of valproic acid in human placenta choriocarcinoma cell line (BeWo). Eur J Pharmacol 2001; 417: 169–76PubMedCrossRefGoogle Scholar
  110. 110.
    Nakamura H, Ushigome F, Koyabu N, et al. Proton gradientdependent transport of valproic acid in human placental brush-border membrane vesicles. Pharm Res 2002; 19: 154–61PubMedCrossRefGoogle Scholar
  111. 111.
    Grassl SM. Human placental brush-border membrane Na+-pantothenate cotransport. J Biol Chem 1992; 267: 22902–6PubMedGoogle Scholar
  112. 112.
    Grassl SM. Human placental brush-border membrane Na+-biotin cotransport. J Biol Chem 1992; 267: 17760–5PubMedGoogle Scholar
  113. 113.
    Pasanen M, Pelkonen O. The expression and environmental regulation of P450 enzymes in human placenta. Crit Rev Toxicol 1994; 24: 211–29PubMedCrossRefGoogle Scholar
  114. 114.
    Marray M. P450-enzymes-inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23: 132–46CrossRefGoogle Scholar
  115. 115.
    Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev 1989; 40: 243–88Google Scholar
  116. 116.
    Thompson EAJ, Siiteri PK. The involvement of human placental microsomal cytochrome P-450 in aromatization. J Biol Chem 1974; 249: 5373–8PubMedGoogle Scholar
  117. 117.
    Hakkola J, Pasanen M, Hukkanen J, et al. Expression of xenobiotic-metabolising cytochrome-P450 forms in human full-term placenta. Biochem Pharmacol 1996; 51: 403–11PubMedCrossRefGoogle Scholar
  118. 118.
    Hakkola J, Raunio H, Purkunen R, et al. Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy. Biochem Pharmacol 1996; 52: 379–83PubMedCrossRefGoogle Scholar
  119. 119.
    Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12: 1–51PubMedCrossRefGoogle Scholar
  120. 120.
    Pasanen M, Helin-Martikainen RL, Pelkonen O, et al. Intrahepatic cholestasis of pregnancy impairs the activity of human placental xenobiotic and steroid metabolising enzymes in vitro. Placenta 1997; 18: 37–41PubMedCrossRefGoogle Scholar
  121. 121.
    Collier AC, Tingle MD, Paxton JW, et al. Metabolizing enzyme localisation and activities in the first trimester human placenta: the effect of maternal and gestational age, smoking and alcohol consumption. Hum Reprod 2002; 17: 2564–72PubMedCrossRefGoogle Scholar
  122. 122.
    Hakkola J, Pasanen M, Pelkonen O, et al. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah-receptor ligands in human placenta and cultured cells. Carcinogenesis 1997; 18: 391–7PubMedCrossRefGoogle Scholar
  123. 123.
    Paakki P, Stockmann H, Rantola M, et al. Maternal drug abuse and human term placental xenobiotic and steroid metabolising enzymes in vitro. Environ Health Perspect 2000; 108: 141–5PubMedCrossRefGoogle Scholar
  124. 124.
    Hincal F. Effects of exposure to air pollution and smoking on the placental aryl hydrocarbon hydroxylase (AHH) activity. Arch Environ Health 1986; 41: 377–83PubMedCrossRefGoogle Scholar
  125. 125.
    Wong TK, Everson RB, Hsu ST. Potent induction of human placental monooxygenase activity by previous dietary exposure to polychlorinated biphenyls and their thermal degradation products. Lancet 1985; I: 721–4CrossRefGoogle Scholar
  126. 126.
    Pasanen M, Taskinen T, Sotaniemi LA, et al. Inhibitor panel studies of human hepatic and placental cytochrome P-450-associated monooxygenase activities. Pharmacol Toxicol 1988; 62: 311–7PubMedCrossRefGoogle Scholar
  127. 127.
    Pasanen M, Pelkonen O. Xenobiotic and steroid-metabolising monooxygenases cataylsed by cytochrome P450 and glutathione S-transferase conjugations in the human placenta and theft relationships to maternal cigarette smoking. Placenta 1990; 11: 75–85PubMedCrossRefGoogle Scholar
  128. 128.
    McRobie DJ, Glover DD, Tracey TS. Effects of gestational and overt diabetes on human placental cytochromes P450 and glutathione S-transferase. Drug Metab Dispos 1998; 26: 367–71PubMedGoogle Scholar
  129. 129.
    Koskela S, Hakkola J, Hukkanen J, et al. Expression of CYP2A genes in human liver and extrahepatic tissues. Biochem Pharmacol 1999; 57: 1407–13PubMedCrossRefGoogle Scholar
  130. 130.
    Pienimäki P, Lampela E, Hakkola J, et al. Pharmacokinetics of oxcarbazepine and carbamazepine in human placenta. Epilepsia 1997; 38: 309–16PubMedCrossRefGoogle Scholar
  131. 131.
    Pasanen M, Haaparanta T, Sundin M, et al. Immunochemical and molecular biochemical studies on human placental cigarette smoke-inducible cytochrome P-450-dependent monooxygenase activities. Toxicology 1990; 62: 175–87PubMedCrossRefGoogle Scholar
  132. 132.
    Pelkonen O, Vähäkangas K, Kärki NT, et al. Genetic and environmental regulation of aryl hydrocarbon hydroxylase in man: studies with liver, lung, placenta, and lymphocytes. Toxicol Pathol 1984; 12: 256–60PubMedCrossRefGoogle Scholar
  133. 133.
    Manchester DK, Gordon SK, Golas CL, et al. Ah receptor in human placenta: stabilization by molybdate and characterization of binding of 2,3,7,8-terachlorodibenzo-p-dioxin, 3-in-ethylcholanthrene, and benzo(a)pyrene. Cancer Res 1987; 36: 4861–8Google Scholar
  134. 134.
    Pelkonen O, Jouppila P, Kärki NT, et al. Attempts to induce drug metabolism in human fetal liver and placenta by the administration of phenobarbital to mothers. Arch Int Pharmacodyn Ther 1973; 202: 288–97PubMedGoogle Scholar
  135. 135.
    Pelkonen O, Arvela P, Kärki NT. 3,4-Benzo(a)pyrene and N-methylalanine metabolising enzymes in the immature human fetus and placenta. Acta Pharmacol Toxicol 1971; 30: 385–95CrossRefGoogle Scholar
  136. 136.
    Pelkonen O, Jouppila P, Kärki NT. Effect of maternal cigarette smoking in 3,4-benzo(a)pyrene and N-methylalanine metabolism in human fetal liver and placenta. Toxicol Appl Pharmacol 1972; 23: 29–37CrossRefGoogle Scholar
  137. 137.
    Gurtoo HL, Williams CI, Gottlieb K, et al. Population distribution of benzo(a)pyrene metabolism in smokers. Int J Cancer 1983; 31: 385–95CrossRefGoogle Scholar
  138. 138.
    Shiverick KT, Salafia C. Cigarette smoking and pregnancy I: ovarian, uterine and placental effects. Placenta 1999; 20: 265–72PubMedCrossRefGoogle Scholar
  139. 139.
    Rasheed A, Himes R, McCarver-May D. Variation in induction of human placental CYP2E1: possible role is susceptibility to fetal alcohol syndrome. Toxicol Appl Pharmacol 1997; 144: 396–400PubMedCrossRefGoogle Scholar
  140. 140.
    Karl P, Gordon B, Leiber C, et al. Acetaldehyde production and transfer in the perfused human placental cotyledon. Science 1988; 242: 273–5PubMedCrossRefGoogle Scholar
  141. 141.
    Vieira I, Pasanen M, Raunio H, et al. Expression of CYP2E1 in human lung and kidney during development and in full-term placenta: a differential methylation of the gene is involved in the regulation process. Pharmacol Toxicol 1998; 83: 183–7PubMedCrossRefGoogle Scholar
  142. 142.
    Nebert DW, Nelson DR, Coon MR, et al. The P450 superfamily: update on new sequences, gene mapping and recommended nomenclature. DNA Cell Biol 1991; 10: 1–14PubMedCrossRefGoogle Scholar
  143. 143.
    Mackenzie P, Owens I, Burchell B, et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 1997; 7: 255–69PubMedCrossRefGoogle Scholar
  144. 144.
    Collier AC, Tingle MD, Keelan JA, et al. A highly sensitive fluorescent microplate method for the determination of UDP-glucuronosyl transferase activity in tissues and placental cell lines. Drug Metab Dispos 2000; 28: 1184–6PubMedGoogle Scholar
  145. 145.
    Ganley N. The expression and localisation of uridine diphosphate glucuronosyltransferase 2B subfamily in human placenta tissue [M.Sc. thesis]. Auckland: University of Auckland, 2001Google Scholar
  146. 146.
    Aitio A. UDP glucuronosyltransferase of the human placenta. Biochem Pharmacol 1974; 23: 2203–5PubMedCrossRefGoogle Scholar
  147. 147.
    Schenker S, Yang Y, Mattiuz E, et al. Olanzapine transfer by human placenta. Clin Exp Pharmacol Physiol 1999; 26: 691–7PubMedCrossRefGoogle Scholar
  148. 148.
    Mannervick B, Widersten M. Human glutathione S-transferases: classification, tissue distribution, structure and functional properties. In: Pacific GM, Fracchia GN, editors. Advances in drug metabolism in man. Luxembourg: Office for Official Publications of the European Communities, 1995: 407–59Google Scholar
  149. 149.
    Nakasa N, Mera N, Ohmori S, et al. Nucleotide sequence of piclass glutathione S-transferase in human fetal liver. Res Commun Mol Pathol Pharmacol 1997; 97: 67–78PubMedGoogle Scholar
  150. 150.
    Guthenburg C, Mannervick B. Glutathione S-transferase (transferase pi) from human placenta is identical or closely related to glutathione S-transferase (transferase pi) from erythrocytes. Biochim Biophys Acta 1981; 661: 255–60CrossRefGoogle Scholar
  151. 151.
    Finnell K, Buehler B, Kerr B, et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-linked teratogenesis. Neurology 1992; 4: 25–31Google Scholar
  152. 152.
    Ratge D, Kohse KP, Steegmuller U, et al. Distribution of free and conjugated catecholamines between plasma, platelets and erythrocytes: different effects of intravenous and oral catecholamine administration. J Pharmacol Exp Ther 1991; 257: 232–8PubMedGoogle Scholar
  153. 153.
    Glatt H, Boeing H, Engelke CE. Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res 2001; 482: 27–40PubMedCrossRefGoogle Scholar
  154. 154.
    Bernier F, Leblanc G, Labrie F, et al. The structure of human estrogen and aryl sulphotransferase gene: two mRNA species issued from a single gene. J Biol Chem 1994; 269: 28200–5PubMedGoogle Scholar
  155. 155.
    Cappiello M, Giuliani L, Rane A, et al. Dopamine sulphotransferase is better developed than p-nitrophenol sulphotransferase in human fetus. Dev Pharmacol Ther 1991; 1991: 83–8Google Scholar
  156. 156.
    Sodha RJ, Glover V, Sandler M. Phenolsulphotransferase in human placenta. Biochem Pharmacol 1983; 32: 1655–7PubMedCrossRefGoogle Scholar
  157. 157.
    Sodha RJ, Schneider H. Sulphate conjugation of beta2-adrenoceptor stimulating drugs by platelet and placental phenol sulphotransferase. Br J Clin Pharmacol 1984; 17: 106–8PubMedCrossRefGoogle Scholar
  158. 158.
    Cappiello M, Franchi M, Rane A, et al. Sulphotransferase and it substrate: adenosine-3′-phosphate-5′-phosphosulphate in human fetal liver and placenta. Dev Pharmacol Ther 1990; 14: 62–5PubMedGoogle Scholar
  159. 159.
    Weigand UW, Chou RC, Maulik D, et al. Assessment of biotransformation during transfer of propoxyphene and acetaminophen across the isolated perfused human placenta. Pediatr Pharmacol 1984; 4: 145–53Google Scholar
  160. 160.
    Kennedy R, Miller R, Bell J, et al. Uptake and distribution of bupivicaine in fetal lambs. Anesthesiology 1986; 65: 247–53PubMedCrossRefGoogle Scholar
  161. 161.
    Faber JJ, Thornburg KL. Placental physiology: structure and function of fetomaternal exchange. New York: Raven Press, 1983Google Scholar
  162. 162.
    Hanshaw-Thomas A, Reynolds F. Placental transfer of bupivicaine, pethidine and lignocaine in the rabbit: effect of umbilical flow rate and protein content. Br J Obstet Gynaecol 1985; 92: 6–12Google Scholar
  163. 163.
    Panigel M, Pascaud M, Brun JL. Une nouvelle technique de perfusion de l’espace intervilleux dans le placenta humain isole. Pathol Biol 1967; 15: 821Google Scholar
  164. 164.
    Brandes JM, Tavolini N, Potter BJ, et al. A new recycling technique for the human placental cotyledon perfusion: application to the studies of the fetomaternal transfer of glucose, insulin, and antipyrine. Am J Obstet Gynecol 1983; 146: 800–6PubMedGoogle Scholar
  165. 165.
    Schneider H, Panigel M, Dancis J. Transfer across the perfused human placenta of antipyrine, sodium, and leucine. Am J Obstet Gynecol 1972; 114: 822–8PubMedGoogle Scholar
  166. 166.
    Schenker S, Dicke J, Johnson RF, et al. Human placental transport of cimetidine. J Clin Invest 1987; 80: 1428–34PubMedCrossRefGoogle Scholar
  167. 167.
    Holcberg G, Sapir O, Huleihel M, et al. Indomethacin activity in the fetal vasculature of normal and meconium exposed human placentae. Eur J Obstet Gynecol 2001; 94: 230–3CrossRefGoogle Scholar
  168. 168.
    Sastry BVR, Hemontolor ME, Olenick M. Prostaglandin E2 in human placenta: its vascular effects and activation of prostaglandin E2 formation by nicotine and cotinine. Pharmacology 1999; 58: 70–86CrossRefGoogle Scholar
  169. 169.
    Frank HG, Morrish DW, Potgens A, et al. Cell culture models of human trophoblast: primary culture of trophoblast: a workshop report. Placenta 2001; 22 Suppl. A: 107–9CrossRefGoogle Scholar
  170. 170.
    Hemmings DG, Lowen B, Sherburne R, et al. Villous trophoblasts cultured on semi-permeable membranes form an effective barrier to the passage of high and low molecular weight particles. Placenta 2001; 22: 70–9PubMedCrossRefGoogle Scholar
  171. 171.
    Liu F, Michael SJ, Kenneth AL. Permeability properties of monolayers of the trophoblast cell line BeWo. Am J Physiol 1997; 273: C1596–604PubMedGoogle Scholar
  172. 172.
    Ampasavate C, Chandorkar GA, Van der Velde DG, et al. Transport and metabolism of opioid peptides across BeWo cells, an in vitro model of the placental barrier. Int J Pharm 2002; 233: 85–98PubMedCrossRefGoogle Scholar
  173. 173.
    Bourget P, Fernandez H, Delouis C, et al. Pharmacokinetics of tobramycin in pregnant women: safety and efficacy of a oncedaily dose regimen. J Clin Pharm Ther 1991; 16: 167–76PubMedCrossRefGoogle Scholar
  174. 174.
    Schneider H. The role of the placenta in the nutrition of the human fetus. Am J Obstet Gynecol 1991; 164: 967–73PubMedGoogle Scholar
  175. 175.
    Boyd RDH, Haworth C, Stacey TE, et al. Permeability of the sheep placenta to unmetabolized polar nonelectrolytes. J Physiol 1976; 256: 617–34PubMedGoogle Scholar
  176. 176.
    Thornburg KL, Faber JJ. Transfer of hydrophilic molecules by placenta and yolk-sac of the guinea pig. Am J Physiol 1977; 33: C111–24Google Scholar
  177. 177.
    King BF. Development and structure of the placenta and fetal membranes of nonhuman primates. J Exp Zool 1993; 266: 528–40PubMedCrossRefGoogle Scholar
  178. 178.
    Wolfgang MJ, Eisele SG, Browne MA, et al. Rhesus monkey placental transgene expression after lentiviral gene transfer into preimplantation embryos. Proc Natl Acad Sci USA 2001; 98: 10728–32PubMedCrossRefGoogle Scholar
  179. 179.
    Patterson TA, Binienda ZK, Newport GD, et al. Transplacental pharmacokinetics and fetal distribution of 2′, 3′-didehydro-3′-deoxythymidine (d4T) and its metabolites in late-term rhesus macaques. Teratology 2000; 62: 93–9PubMedCrossRefGoogle Scholar
  180. 180.
    Tuntland T, Odinecs A, Pereira CM, et al. In vitro models to predict the in vivo mechanism, rate and extent of placental transfer of dideoxynucleoside drugs against human immunodeficiency virus. Am J Obstet Gynecol 1999; 180: 198–206PubMedCrossRefGoogle Scholar
  181. 181.
    Bonati M, Bortolus R, Marchetti F, et al. Drug use in pregnancy: an overview of epidemiological (drug use) studies. Eur J Clin Pharmacol 1990; 38: 325–8PubMedCrossRefGoogle Scholar
  182. 182.
    Sabo A, Stanulovic M, Jakovljevic V, et al. Collaborative study on drug use in pregnancy: the results of the follow-up 10 years after (Novi Sad Centre). Pharmacoepidemiol Drug Saf 2001; 10: 229–35PubMedCrossRefGoogle Scholar
  183. 183.
    Neiburg P, Marks JS, McLaren NM, et al. The fetal tobacco syndrome. JAMA 1985; 253: 2998–9CrossRefGoogle Scholar
  184. 184.
    Cnattingius S, Axelsson G, Eklund G, et al. Smoking, maternal age and fetal growth. Obstet Gynecol 1985; 66: 449–52PubMedGoogle Scholar
  185. 185.
    Page KR, Bush P, Abramovich DR, et al. The effects of smoking on placental membranes. J Memb Sci 2002; 206: 243–52CrossRefGoogle Scholar
  186. 186.
    Bush PG, Mayhew TM, Abramovich DR, et al. A quantitative study on the effects of maternal smoking on placental morphology and cadmium concentration. Placenta 2000; 21: 247–56PubMedCrossRefGoogle Scholar
  187. 187.
    Shepard TH. Catalog of teratogenic agents. Baltimore: John Hopkins University Press, 2001Google Scholar
  188. 188.
    Lehtovirta P, Fross M, Rauramo I, et al. Acute effects of nicotine on fetal heart rate variability. Br J Obstet Gynaecol 1983; 90: 710–5PubMedCrossRefGoogle Scholar
  189. 189.
    Manning FA, Feyerabend C. Cigarette smoking and fetal breathing movements. Br J Obstet Gynaecol 1976; 83: 262–70PubMedCrossRefGoogle Scholar
  190. 190.
    Pastrakuljic A, Schwartz R, Simone C, et al. Transplacental transfer and biotransformation studies of nicotine in the human placental cotyledon perfused in vitro. Life Sci 1998; 63: 2333–42PubMedCrossRefGoogle Scholar
  191. 191.
    Sastry BVR, Chance MB. Biotransformation of nicotine in the perfused human placenta [abstract]. Placenta 1994; 15: A56Google Scholar
  192. 192.
    Kerenyi TD, Gleicher N, Meller J, et al. Transplacental cardioversion of intrauterine superventricular tachycardia with digitalis. Lancet 1980; II: 393–4CrossRefGoogle Scholar
  193. 193.
    Kleinman CS, Copel JA. Fetal cardiac arrhythmias: diagnosis and therapy. In: Creasy RK, Resnick R, editors. Maternal-fetal medicine: principles and practice. Philadelphia: WB Saunders, 1994: 326–41Google Scholar
  194. 194.
    Southall DP, Richards J, Hardwick R-A, et al. Prospective study of fetal heart rate and rhythm patterns. Arch Dis Child 1980; 55: 506–11PubMedCrossRefGoogle Scholar
  195. 195.
    Meijboom EJ, van Engelen AD, van de Beck EW, et al. Fetal arrhythmias. Curr Opin Cardiol 1994; 9: 97–102PubMedCrossRefGoogle Scholar
  196. 196.
    Ito S. Transplacental treatment of fetal tachycardia: implications of drug transporting proteins in placenta. Semin Perinatol 2001; 25: 196–201PubMedCrossRefGoogle Scholar
  197. 197.
    Azancot-Benisty A, Jacqz-Aigrain E, Guirgis NM, et al. Clinical and pharmacologic study of fetal supraventricular tachyarrhythmias. J Pediatr 1992; 121: 608–13PubMedCrossRefGoogle Scholar
  198. 198.
    Younis JS, Granat M. Insufficient transplacental digoxin transfer in severe fetal hydrops fetalis. Am J Obstet Gynecol 1987; 157: 1268–9PubMedGoogle Scholar
  199. 199.
    Weiner CP, Thompson MIB. Direct treatment of fetal supraventricular tachycardia after failed transplacental therapy. Am J Obstet Gynecol 1988; 158: 570–3PubMedGoogle Scholar
  200. 200.
    Arnoux P, Seyral P, Llurens M, et al. Amiodarone and digoxin for refractory fetal tachycardia. Am J Cardiol 1987; 59: 166–7PubMedCrossRefGoogle Scholar
  201. 201.
    Spinnato JA, Shaver DC, Flinn GS, et al. Fetal supraventricular tachycardia: in utero therapy with digoxin and quinidine. Obstet Gynecol 1984; 64: 730–5PubMedGoogle Scholar
  202. 202.
    Parilla BV, Grobman WA, Holtzman RB, et al. Indomethacin tocolysis and risk of necrotizing enterocolitis. Obstet Gynecol 2000; 96: 120–3PubMedCrossRefGoogle Scholar
  203. 203.
    Abramov Y, Nadjari M, Weinstein D, et al. Indomethacin for preterm labor: a randomized comparison of vaginal and rectaloral routes. Obstet Gynecol 2000; 95: 482–6PubMedCrossRefGoogle Scholar
  204. 204.
    Nielsen GL, Sorensen HT, Larsen H, et al. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001; 322: 266–70PubMedCrossRefGoogle Scholar
  205. 205.
    Ericson A, Kallen BA. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001; 15: 371–5PubMedCrossRefGoogle Scholar
  206. 206.
    Schoenfeld A, Bar Y, Merlob P, et al. NSAIDs: maternal and fetal considerations. Am J Reprod Immunol 1992; 28: 141–7PubMedGoogle Scholar
  207. 207.
    McGarrity C, Samani N, Beck F, et al. The effect of sodium salicylate on the rat embryo in culture: an in vitro model for the morphological assessment of teratogenicity. J Anat 1981; 133: 257–69PubMedGoogle Scholar
  208. 208.
    Chan LY, Chiu PY, Siu SS, et al. A study of diclofenac-induced teratogenicity during organogenesis using a whole rat embryo culture model. Hum Reprod 2001; 16: 2390–3PubMedGoogle Scholar
  209. 209.
    Foulon O, Jaussely C, Repetto M, et al. Postnatal evolution of supernumerary ribs in rats after a single administration of sodium salicylate. J Appl Toxicol 2000; 20: 205–9PubMedCrossRefGoogle Scholar
  210. 210.
    Nelson JL, Ostensen M. Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am 1997; 23: 195–212PubMedCrossRefGoogle Scholar
  211. 211.
    Akbaraly R, Leng JJ, Brachet-Liermain A, et al. Trans-placental transfer of four anti-inflammatory agents: a study carried out by in vitro perfusion. J Gynecol Obstet Biol Reprod (Paris) 1981; 10: 7–11Google Scholar
  212. 212.
    Lampela ES, Nuutinen LH, Ala-Kokko TI, et al. Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model. Am J Obstet Gynecol 1999; 180: 174–80PubMedCrossRefGoogle Scholar
  213. 213.
    Siu SSN, Yeung JHK, Lau TK. A study on placental transfer of diclofenac in first trimester of human pregnancy. Hum Reprod 2000; 15: 2423–5PubMedCrossRefGoogle Scholar
  214. 214.
    Slattery MM, Friel AM, Healy DG, et al. Uterine relaxant effects of cyclooxygenase-2 inhibitors in vitro. Obstet Gynecol 2001; 98: 563–9PubMedCrossRefGoogle Scholar
  215. 215.
    Sakai M, Tanebe K, Sasaki Y, et al. Evaluation of the tocolytic effect of a selective cyclooxygenase-2 inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery. Mol Hum Reprod 2001; 7: 595–602PubMedCrossRefGoogle Scholar
  216. 216.
    Gross G, Imamura T, Vogt SK, et al. Inhibition of cyclooxyganase-2 prevents inflammation-mediated preterm labor in the mouse. Am J Physiol Regul Integr Comp Physiol 2000; 278: R1415–23PubMedGoogle Scholar
  217. 217.
    Takahashi Y, Roman C, Chemtob S, et al. Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo. Am J Physiol Regul Integr Comp Physiol 2000; 278: R1496–505PubMedGoogle Scholar
  218. 218.
    Sawdy R, Slater D, Fisk N, et al. Use of cyclo-oxygenase type-2-selective non-steroidal anti-inflammatory agent to prevent preterm delivery. Lancet 1997; 350: 265–6PubMedCrossRefGoogle Scholar
  219. 219.
    Khan KN, Stanfield KM, Dannenberg A, et al. Cyclooxygenase-2 expression in the developing human kidney. Pediatr Dev Pathol 2001; 4: 461–6PubMedCrossRefGoogle Scholar
  220. 220.
    Lassus P, Wolff H, Andersson S. Cyclooxygenase-2 in human perinatal lung. Pediatr Res 2000; 47: 602–5PubMedCrossRefGoogle Scholar
  221. 221.
    Maslinska D, Kaliszek A, Opertowska J, et al. Constitutive expression of cyclooxygenase-2 (COX-2) in developing brain: a. choroid plexus in human fetuses. Folia Neuropathol 1999; 37: 287–91PubMedGoogle Scholar
  222. 222.
    Newell ML. Mechanism and timing of mother-to-child transmission of HIV-1. AIDS 1998; 12: 831–7PubMedCrossRefGoogle Scholar
  223. 223.
    Mofenson LM, Lambert JS, Stiehm ER, et al. Pediatric AIDS Clinical Trials Group Study 185 Team. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. N Engl J Med 1999; 341: 385–93PubMedCrossRefGoogle Scholar
  224. 224.
    Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331: 1173–80PubMedCrossRefGoogle Scholar
  225. 225.
    Madelbrot L, Peyavin G, Firtion G, et al. Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women. Am J Obstet Gynecol 2001; 184: 153–8CrossRefGoogle Scholar
  226. 226.
    Casey BM, Bawdon RE. Placental transfer of ritonavir with zidovudine in the ex vivo placental perfusion model. Am J Obstet Gynecol 1998; 179: 758–61PubMedCrossRefGoogle Scholar
  227. 227.
    Forestier F, de Renty P, Peytavin G, et al. Maternal-fetal transfer of saquinavir studied in the ex vivo placental perfusion model. Am J Obstet Gynecol 2001; 185: 178–81PubMedCrossRefGoogle Scholar
  228. 228.
    Marzolini C, Rudin C, Decosterd LA, et al. Transplacental passage of protease inhibitors at delivery. AIDS 2002; 16: 889–93PubMedCrossRefGoogle Scholar
  229. 229.
    Minkoff H, Augenbraun M. Antiretroviral therapy for pregnant women. Am J Obstet Gynecol 1997; 176: 478–89PubMedCrossRefGoogle Scholar
  230. 230.
    Pascual MJ, Macias RIR, Garcia-Del-Pozo J, et al. Enhanced efficiency of the placental barrier to cisplatin through binding to glycocholic acid. Anticancer Res 2001; 21: 2703–8PubMedGoogle Scholar
  231. 231.
    Marin JJG, Bravo P, El-Mir MYA, et al. ATP-dependent bile acid transport across the microvillous membrane of human term trophoblast. Am J Physiol 1995; 268: G685–94PubMedGoogle Scholar
  232. 232.
    Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969; 45: 515–23PubMedCrossRefGoogle Scholar
  233. 233.
    Spinillo A, Capuzzo E, Ometto A, et al. Value of antenatal corticosteroid therapy in preterm birth. Early Hum Dev 1995; 42: 37–47PubMedCrossRefGoogle Scholar
  234. 234.
    Ward RM. Pharmacologic enhancement of fetal lung maturation. Clin Perinatal 1994; 21: 523–42Google Scholar
  235. 235.
    Ballard PL, Ballard RA. Scientific basis and theapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995; 173: 254–62PubMedCrossRefGoogle Scholar
  236. 236.
    Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990; 97: 11–25PubMedCrossRefGoogle Scholar
  237. 237.
    Natlonal Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement 1994 Feb 28–Mar 2; 12(2): 1–24Google Scholar
  238. 238.
    Wright LL, Verter J, Younes N, et al. Antenatal corticosteroid administration and neonatal outcome in very low birthweight infants: The NICHD Neonatal Research Network. Am J Obstet Gynecol 1995; 173: 269–74PubMedCrossRefGoogle Scholar
  239. 239.
    Horbar JD. Antenatal corticosteroid treatment and neonatal outcomes for infants 501 to 1500gm in the Vermont-Oxford Trials Network. Am J Obstet Gynecol 1995; 173: 275–81PubMedCrossRefGoogle Scholar
  240. 240.
    Anderson DF, Stock MK, Rankin JHG. Placental transfer of dexamethasone in near-term sheep. J Dev Physiol 1979; 1: 431–6PubMedGoogle Scholar
  241. 241.
    Varma DR. Investigation of the maternal to fetal serum concentration gradient of dexamethasone in the rat. Br J Pharmacol 1986; 88: 815–20PubMedCrossRefGoogle Scholar
  242. 242.
    Smith MA, Thomford PJ, Mattison DR, et al. Transport and metabolism of dexamethasone in the dually perfused human placenta. Reprod Toxicol 1988; 2: 37–43PubMedCrossRefGoogle Scholar
  243. 243.
    Levitz M, Jansen V, Dancis J. The transfer and metabolism of corticosteroids in the perfused human placenta. Am J Obstet Gynecol 1978; 132: 363–6PubMedGoogle Scholar
  244. 244.
    De Kloet ER. Why dexamethasone poorly penetrates in brain. Stress 1997; 2: 13–20PubMedCrossRefGoogle Scholar
  245. 245.
    Maillefert JF, Duchamp O, Solary E, et al. Effects of cyclosporin at various concentrations on dexamethasone intracellular uptake in multidrug resistant cells. Ann Rheum Dis 2000; 59: 146–8PubMedCrossRefGoogle Scholar
  246. 246.
    Meijer OC, de Lange EC, Breimer DD, et al. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 1998; 139: 1789–93PubMedCrossRefGoogle Scholar
  247. 247.
    Coutelle C, Douar AM, Colledge W, et al. The challenge of fetal gene therapy. Nat Med 1995; 1: 864–6PubMedCrossRefGoogle Scholar
  248. 248.
    Sawai K, Meruelo D. Cell specific transfection of choriocarcinoma cells by using Sindbis virus hCG expressing chimeric vector. Biochem Biophys Res Commun 1998; 248: 315–23PubMedCrossRefGoogle Scholar
  249. 249.
    Heikkila A, Myllynen P, Keski-Nisula L, et al. Gene transfer to human placenta ex vivo: a novel application of dual perfusion of human placental cotyledon. Am J Obstet Gynecol 2002; 186: 1046–51PubMedCrossRefGoogle Scholar
  250. 250.
    Rosen TS, Pippenger CE. Disposition of methadone and its relationship to severity of withdrawal in the newborn. Addict Dis 1975; 2: 169–78PubMedGoogle Scholar
  251. 251.
    Fisher G, Gombas W, Eder H, et al. Buprenorphine versus methadone maintenance for the treatment of opioid dependence. Addiction 1999; 94: 1337–47CrossRefGoogle Scholar
  252. 252.
    Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid dependence. JAMA 1992; 267: 2750–5PubMedCrossRefGoogle Scholar
  253. 253.
    Ling W, Charuvastra C, Collins J. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction 1998; 93: 475–586PubMedCrossRefGoogle Scholar
  254. 254.
    Fisher G, Rolley JE, Eder H, et al. Treatment of opioiddependent pregnant women with buprenorphine. Addiction 2000; 95: 239–44CrossRefGoogle Scholar
  255. 255.
    Marquet P, Chevrel J, Lavignasse P, et al. Buprenorphine withdrawal in a newborn. Clin Pharmacol Ther 1997; 62: 569–71PubMedCrossRefGoogle Scholar
  256. 256.
    Ganapathy V, Prasad PD, Ganapathy ME, et al. Drags of abuse and placental transport. Adv Drag Deliv Rev 1999; 1: 99–110CrossRefGoogle Scholar
  257. 257.
    Ganapathy V, Ramamoorthy S, Leibach FH. Transport and metabolism of monoamines in the human placenta. Trophoblast Res 1993; 7: 35–51Google Scholar
  258. 258.
    Ganapathy V, Leibach FH. Placental biogenic amines and their transporters. In: Sastry BVR, editor. Placental toxicology. Boca Raton: CRC Press, 1995: 161–74Google Scholar
  259. 259.
    Fergusson DM, Horwood LJ, Northstone K, et al. Maternal use of cannabis and pregnancy outcome. BJOG 2002; 109: 21–7PubMedCrossRefGoogle Scholar
  260. 260.
    Harbison RD, Mantilla-Plata B. Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol. J Pharmacol Exp Ther 1972; 180: 446–53PubMedGoogle Scholar
  261. 261.
    Fried PA, Smith AM. A literature review of the consequences of prenatal marihuana exposure: an emerging theme of a deficiency in aspects of executive function. Neurotoxicol Teratol 2001; 23: 1–11PubMedCrossRefGoogle Scholar
  262. 262.
    Goldschmidt L, Day NL, Richardson GA. Effects of prenatal marijuana exposure on child behaviour problems at age 10. Neurotoxicol Teratol 2000; 22: 325–36PubMedCrossRefGoogle Scholar
  263. 263.
    Bailey JR, Cunny HC, Paule M, et al. Fetal disposition of delta 9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey. Toxicol Appl Pharmacol 1987; 90: 315–21PubMedCrossRefGoogle Scholar
  264. 264.
    Abrams RM, Cook CE, Davis KH, et al. Plasma delta-9-tetrahydrocannabinol in pregnant sheep and fetus after inhalation of smoke from a marijuana cigarette. Alcohol Drag Res 1985/1986; 6: 361–9Google Scholar
  265. 265.
    Blackard C, Tennes K. Human placental transfer of cannabinoids [letter]. N Engl J Med 1984; 20: 797Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Michael R. Syme
    • 1
  • James W. Paxton
    • 1
  • Jeffrey A. Keelan
    • 1
    Email author
  1. 1.Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand

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