Assessing drug transport across the human placental barrier: From in Vivo and in Vitro measurements to the Ex Vivo perfusion method and in silico techniques

Current Pharmaceutical Biotechnology

Volumn 12, Issue 5, 2011, Pages 804-813

  Giaginis, Constantinos ^a,b   Tsantili Kakoulidou, Anna ^b   Theocharis, Stamatios ^a  

^a UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

^b UNIVERSITY OF ATHENS   (Greece)

Author keywords

Biopharmaceuticals; Ex vivo placental perfusion; In silico modeling; Physicochemical properties; Placental transfer; Risk assessment

Indexed keywords

ANESTHETIC AGENT; ANTICONVULSIVE AGENT; ANTIDIABETIC AGENT; BREAST CANCER RESISTANCE PROTEIN; CARRIER PROTEIN; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 2; GLYCOPROTEIN P; HUMAN INSULIN; INTETUMUMAB; MONOCARBOXYLATE TRANSPORTER; MULTIDRUG RESISTANCE PROTEIN; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 3; NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR; NORADRENALIN TRANSPORTER; ORGANIC CATION TRANSPORTER 2; ORGANIC CATION TRANSPORTER 3; PROTEINASE INHIBITOR; SEROTONIN TRANSPORTER;

ACTIVE TRANSPORT; CELL IMMORTALIZATION; DRUG SAFETY; DRUG TRANSPORT; EX VIVO STUDY; EXPLANT; FETOTOXICITY; FETUS RISK; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MEASUREMENT; MOLECULAR SIZE; NONHUMAN; PASSIVE TRANSPORT; PLACENTA PERFUSION; PLACENTAL TRANSFER; PREGNANCY; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; RISK ASSESSMENT; TECHNIQUE; TROPHOBLAST; VALIDATION PROCESS; XENOBIOTIC METABOLISM;

EID: 79955604531     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/138920111795470930     Document Type: Review

References (106)

1. Kaufmann, P.; Frank H.G. Placental development. In: Fetal and Neonatal Physiology; Polin, R.A.; Fox, W.W.; Abman, S.H.; Eds.; Saunders; London, 2006, pp. 85-97.
2. Evain-Brion, D.; Malassine, A. Human placenta as an endocrine organ. Growth Horm. IGF Res., 2003, 13(Suppl. A), S34-S37.
3. Cross, J.C. Placental function in development and disease. Reprod. Fertil. Dev., 2006, 18(1-2), 71-76.
4. Collins, T.F. History and evolution of reproductive and developmental toxicology guidelines. Curr. Pharm. Des., 2006, 12(12), 1449-1465.
5. Younglai, E.V.; Wu, Y.J.; Foster, W.G. Reproductive toxicology of environmental toxicants: emerging issues and concerns. Curr. Pharm. Des., 2007, 13(29), 3005-3019.
6. van der Aa, E.M.; Peereboom-Stegeman, J.H.; Noordhoek, J.; Gribnau, F.W.; Russel, F.G. Mechanisms of drug transfer across the human placenta. Pharm. World Sci., 1998, 20(4), 139-148.
7. Schantz, S.L. Developmental neurotoxicity of PCBs in humans: what do we know and where do we go from here? Neurotoxicol. Teratol., 1996, 18(3), 217-227.
8. Tilson, H.A.; Kodavanti, P.R.; Mundy, W.R.; Bushnell, P.J. Neurotoxicity of environmental chemicals and their mechanism of action. Toxicol. Lett., 1998, 102-103, 631-635.
9. Garcia-Bournissen, F.; Rokach, B.; Karaskov, T.; Koren, G. Cocaine detection in maternal and neonatal hair: implications to fetal toxicology. Ther. Drug Monit., 2007, 29(1), 71-76.
10. Burton, G.J.; Jauniaux, E.; Charnock-Jones, D.S. Human early placental development: potential roles of the endometrial glands. Placenta, 2007, 28(Suppl. A), S64-S69.
11. Cross, J.C.; Anson-Cartwright, L.; Scott, I.C. Transcription factors underlying the development and endocrine functions of the placenta. Recent Prog. Horm. Res., 2002, 57, 221-234.
12. Aplin, J.D.; Jones, C.J.; Harris, L.K. Adhesion molecules in human trophoblast-a review. I. Villous trophoblast. Placenta, 2009, 30(4), 293-298.
13. Kingdom, J.; Huppertz, B.; Seaward, G.; Kaufmann, P. Development of the placental villous tree and its consequences for fetal growth. Eur. J. Obstet. Gynecol. Reprod. Biol., 2000, 92(1), 35-43.
14. Fowden, A. L; Forhead, A.J. Endocrine regulation of feto-placental growth. Horm. Res., 2009, 72(5), 257-265.
15. Osol, G.; Mandala, M. Maternal uterine vascular remodeling during pregnancy. Physiology, (Bethesda) 2009, 24, 58-71.
16. Enders, A.C.; Blankenship, T.N. Comparative placental structure. Adv. Drug Deliv. Rev., 1999, 38(1), 3-15.
17. Bazer, F.W.; Spencer, T.E.; Johnson, G.A.; Burghardt, R.C.; Wu, G. Comparative aspects of implantation. Reproduction, 2009, 138(2), 195-209.
18. Mayhew, T.M. A stereological perspective on placental morphology in normal and complicated pregnancies. J. Anat., 2009, 215(1), 77-90.
19. Klieger, C.; Pollex, E.; Kazmin, A.; Koren, G. Hypoglycemics: pharmacokinetic considerations during pregnancy. Ther. Drug Monit., 2009, 31(5), 533-541.
20. Holcberg, G.; Tsadkin-Tamir, M.; Sapir, O.; Huleihel, M.; Mazor, M.; Ben Zvi, Z. New aspects in placental drug transfer. Isr. Med. Assoc. J., 2003, 5(12), 873-876.
21. Garcia-Bournissen, F.; Feig, D.S.; Koren, G. Maternal-fetal transport of hypoglycaemic drugs. Clin. Pharmacokinet., 2003, 42(4), 303-313.
22. Gedeon, C.; Koren, G. Designing pregnancy centered medications: drugs which do not cross the human placenta. Placenta, 2006, 27(8), 861-868.
23. Reynolds, F.; Knott, C. Pharmacokinetics in pregnancy and placental drug transfer. Oxf. Rev. Reprod. Biol., 1989, 11, 389-449.
24. Audus, K.L. Controlling drug delivery across the placenta. Eur. J. Pharm. Sci., 1999, 8(3), 161-165.
25. Hovinga, C.A.; Pennell, P.B. Antiepileptic drug therapy in pregnancy II: fetal and neonatal exposure. Int. Rev. Neurobiol., 2008, 83, 241-258.
26. Gulati, A.; Gerk, P.M. Role of placental ATP-binding cassette (ABC) transporters in antiretroviral therapy during pregnancy. J. Pharm. Sci., 2009, 98(7), 2317-2335.
27. Anderson, G.D. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin. Pharmacokinet., 2005, 44(10), 989-1008.
28. Vähäkangas, K.; Myllynen, P. Drug transporters in the human blood-placental barrier. Br. J. Pharmacol., 2009, 158(3), 665-678.
29. Ganapathy, V.; Prasad, P.D. Role of transporters in placental transfer of drugs. Toxicol. Appl. Pharmacol., 2005, 207(2 Suppl.), 381-387.
30. Myren, M.; Mose, T.; Mathiesen, L.; Knudsen, L.E. The human placenta-an alternative for studying foetal exposure. Toxicol. in Vitro, 2007, 21(7), 1332-1340.
31. Merchant, S.J.; Crocker, I.P.; Baker, P.N.; Tansinda, D.; Davidge, S.T.; Guilbert, L.J. Matrix metalloproteinase release from placental explants of pregnancies complicated by intrauterine growth restriction. J. Soc. Gynecol. Investig., 2004, 11(2), 97-103.
32. Zhou, Y.; Bianco, K.; Huang, L.; Nien, J.K.; McMaster, M.; Romero, R.; Fisher, S.J. Comparative analysis of maternal-fetal interface in preeclampsia and preterm labor. Cell. Tissue Res., 2007, 329(3), 559-569.
33. Hawfield, A.; Freedman, B.I. Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection. Ther. Adv. Cardiovasc. Dis., 2009, 3(1), 65-73.
34. Vähäkangas, K.; Myllynen, P. Experimental methods to study human transplacental exposure to genotoxic agents. Mutat. Res., 2006, 608(2), 129-135.
35. Jauniaux, E.; Burton, G.J. Morphological and biological effects of maternal exposure to tobacco smoke on the feto-placental unit. Early Hum. Dev., 2007, 83(11), 699-706.
36. Carter, A.M. Animal models of human placentation-a review. Placenta, 2007, 28(Suppl. A), S41-S47.
37. Georgiades, P.; Ferguson-Smith, A.C.; Burton, G.J. Comparative developmental anatomy of the murine and human definitive placentae. Placenta, 2002, 23(1), 3-19.
38. Botting, J. The history of thalidomide. Drug New Perspect., 2002, 15(9), 604-611.
39. Leiser, R.; Kaufmann, P. Placental structure: in a comparative aspect. Exp. Clin. Endocrinol., 1994, 102(3), 122-134.
40. Faber, J.J. Review of flow limited transfer in the placenta. Int. J. Obstet. Anesth., 1995, 4(4), 230-237.
41. Myllynen, P.; Pasanen, M.; Pelkonen, O. Human placenta: a human organ for developmental toxicology research and biomonitoring. Placenta, 2005, 26(5), 361-371.
42. Bode, C.J.; Jin, H.; Rytting, E.; Silverstein, P.S.; Young, A.M.; Audus, K.L. In vitro models for studying trophoblast transcellular transport. Methods Mol. Med., 2006, 122, 225-239.
43. Kliman, H.J.; Nestler, J.E.; Sermasi, E.; Sanger, J.M.; Strauss, J.F.3rd. Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology, 1986, 118(4), 1567-1582.
44. Hemmings, D.G.; Lowen, B.; Sherburne, R.; Sawicki, G.; Guilbert, L.J. Villous trophoblasts cultured on semi-permeable membranes form an effective barrier to the passage of high and low molecular weight particles. Placenta, 2001, 22(1), 70-79.
45. King, A.; Thomas, L.; Bischof, P. Cell culture models of trophoblast II: trophoblast cell lines-a workshop report. Placenta, 2000, 21(Suppl. A), S113-S119.
46. Wadsack, C.; Hrzenjak, A.; Hammer, A.; Hirschmugl, B.; Levak-Frank, S.; Desoye, G.; Sattler, W.; Malle, E. Trophoblast-like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins. Eur. J. Biochem., 2003, 270(3), 451-462.
47. Sullivan, M.H. Endocrine cell lines from the placenta. Mol. Cell. Endocrinol., 2004, 228(1-2), 103-119.
48. Liu, F.; Soares, M. J; Audus, K.L. Permeability properties of monolayers of the human trophoblast cell line BeWo. Am. J. Physiol., 1997, 273(5Pt1), C1596-C1604.
49. Shi, F.; Soares, M.J.; Avery, M.; Liu, F.; Zhang, X.; Audus, K.L. Permeability and metabolic properties of a trophoblast cell line (HRP-1) derived from normal rat placenta. Exp. Cell. Res., 1997, 234(1), 147-155.
50. Sastry, B.V. Techniques to study human placental transport. Adv. Drug Deliv. Rev., 1999, 38(1), 17-39.
51. Miller, R.K.; Genbacev, O.; Turner, M.A.; Aplin, J.D.; Caniggia, I.; Huppertz, B. Human placental explants in culture: approaches and assessments. Placenta, 2005, 26(6), 439-448.
52. Syme, M.R.; Paxton, J.W.; Keelan, J.A. Drug transfer and metabolism by the human placenta. Clin. Pharmacokinet., 2004, 43(8), 487-514.
53. Di Santo, S.; Malek, A.; Sager, R.; Andres, A.C.; Schneider, H. Trophoblast viability in perfused term placental tissue and explant cultures limited to 7-24 hours. Placenta, 2003, 24(8-9), 882-894.
54. Schneider, H.; Panigel, M.; Dancis, J. Transfer across the perfused human placenta of antipyrine, sodium and leucine. Am. J. Obstet. Gynecol., 1972, 114(6), 822-828.
55. Miller, R.K.; Wier, P.J.; D' Gregorio, R.P.; Eisenmann, C.; di Sant'Agnese, P.A.; Shah Y., Neth-Jessee, L. Human dual placental perfusions-criteria for toxicity evaluations. Methods Toxicol., 1993, 3B, 246-259.
56. Ala-Kokko, T.I.; Myllynen, P.; Vähäkangas, K. Ex vivo perfusion of the human placental cotyledon: implications for anesthetic pharmacology. Int. J. Obstet. Anesth., 2000, 9(1), 26-38.
57. Keller, J.M.; Krohmer, J.S. Insulin transfer in the isolated human placenta. Obstet. Gynecol., 1968, 32(1), 77-80.
58. Menon, R.K.; Cohen, R.M.; Sperling, M.A.; Cutfield, W.S.; Mimouni, F.; Khoury, J.C. Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia. N. Engl. J. Med., 1990, 323(5), 309-315.
59. Myllynen, P.; Vähäkangas, K. An examination whether human placental perfusion allows accurate prediction of placental drug transport: studies with diazepam. J. Pharmacol. Toxicol. Methods, 2002, 48(3), 131-138.
60. Bourget, P.; Roulot, C.; Fernandez, H. Models for placental transfer studies of drugs. Clin. Pharmacokinet., 1995, 28(2), 161-180.
61. Valerio, L.G. Jr. Special issue on safety assessment. Toxicol. Appl. Pharmacol., 2010, 243(2), 123-124.
62. Valerio, L.G. Jr. In silico toxicology for the pharmaceutical sciences. Toxicol. Appl. Pharmacol., 2009, 241(3), 356-370.
63. Simon-Hettich, B.; Rothfuss, A.; Steger-Hartmann, T. Use of computer-assisted prediction of toxic effects of chemical substances. Toxicology, 2006, 224(1-2), 156-162.
64. Tropsha, A.; Golbraikh, A. Predictive QSAR modeling workflow, model applicability domains, and virtual screening. Curr. Pharm. Des., 2007, 13(34), 3494-3504.
65. Vedani, A.; Dobler, M.; Lill, M.A. In silico prediction of harmful effects triggered by drugs and chemicals. Toxicol. Appl. Pharmacol., 2005, 207(2 Suppl.), S398-S407.
66. Vedani, A.; Dobler, M.; Lill, M.A. The challenge of predicting drug toxicity in silico. Basic Clin. Pharmacol. Toxicol., 2006, 99(3), 195-208.
67. Zvinavashe, E.; Murk, A.J.; Rietjens, I.M. Promises and pitfalls of quantitative structure-activity relationship approaches for predicting metabolism and toxicity. Chem. Res. Toxicol., 2008, 21(12), 2229-2236.
68. Dominy, B.N. Molecular recognition and binding free energy calculations in drug development. Curr. Pharm. Biotechnol., 2008, 9(2), 87-95.
69. Villoutreix, B.O.; Bastard, K.; Sperandio, O.; Fahraeus, R.; Poyet, J.L.; Calvo, F.; Déprez, B.; Miteva, M.A. In silico-in vitro screening of protein-protein interactions: towards the next generation of therapeutics. Curr. Pharm. Biotechnol., 2008, 9(2), 103-122.
70. Cronin, M.T.; Dearden, J.C.; Walker, J.D. Worth, A.P. Quantitative structure-activity relationships for human health effects: commonalities with other endpoints. Environ. Toxicol. Chem., 2003, 22(8), 1829-1843.
71. Hewitt, M.; Ellison, C.M.; Enoch, S.J.; Madden, J.C.; Cronin, M.T. Integrating (Q)SAR models, expert systems and read-across approaches for the prediction of developmental toxicity. Reprod. Toxicol., 2010, 30(1), 147-160.
72. Cronin, M.T.D.; Worth, A.P. (Q)SARs for predicting effects relating to reproductive toxicity. QSAR Comb. Sci., 2008, 27(1), 91-100.
73. Yamashita, F.; Hashida, M. In silico approaches for predicting ADME properties of drugs. Drug Metab. Pharmacokinet., 2004, 19(5), 327-338.
74. Mälkiä, A.; Murtomäki, L.; Urtti, A.; Kontturi, K. Drug permeation in biomembranes: in vitro and in silico prediction and influence of physicochemical properties. Eur. J. Pharm. Sci., 2004, 23(1), 13-47.
75. Pacifici, G.M.; Nottoli, R. Placental transfer of drugs administered to the mother. Clin. Pharmcokinet., 1995, 28(3), 235-269.
76. Pacifici, G.M. Transfer of antivirals across the human placenta. Early Hum. Dev., 2005, 81(8), 647-654.
77. Pacifici, G.M. Placental transfer of antibiotics administered to the mother: a review. Int. J. Clin. Pharmacol. Ther., 2006, 44(2), 57-63.
78. Giaginis, C.; Zira, A.; Theocharis, S.; Tsantili-Kakoulidou, A. Simple physicochemical properties as effective filters for risk estimation of drug transport across the human placental barrier. Rev. Clin. Pharmacol. Pharmacokin. (Int. Edition), 2008, 22(2), 146-148.
79. Tuntland, T.; Odinecs, A.; Pereira, C.M.; Nosbisch, C.; Unadkat, J.D. 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(1 Pt 1), 198-206.
80. Akbaraly, J.P.; Leng, J.J.; Bozler, G.; Seydel, J.K. Quantitative relationship between tranplacental transfer physicochemical properties of a series of heterogenous drugs. In: Proceeding of the Fifth European Symposium on Quantitative Structure-Activity Relationships, Federal Republic of Germany, Bad Segeberg, Weinheim: VCH, Verlagsgeselischaft, 1985, pp. 313-317.
81. Elliott, B.D.; Schenker, S.; Langer, O.; Johnson, R.; Prihoda, T. Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am. J. Obstet. Gynecol., 1994, 171(3), 653-660.
82. Koren, G. Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod. Toxicol., 2001, 15(3), 227-229.
83. Hewitt, M.; Madden, J.C.; Rowe, P.H.; Cronin, M.T. Structurebased modelling in reproductive toxicology: (Q)SARs for the placental barrier. SAR QSAR Environ. Res., 2007, 18(1-2), 57-76.
84. Giaginis, C.; Zira, A.; Theocharis, S.; Tsantili-Kakoulidou, A. Application of quantitative structure-activity relationships for modeling drug and chemical transport across the human placenta barrier: a multivariate data analysis approach. J. Appl. Toxicol., 2009, 29(8), 724-733.
85. Giaginis, C.; Theocharis, S.; Tsantili-Kakoulidou, A. Quantitative structure-activity relationships for PPAR-gamma binding and gene transactivation of tyrosine-based agonists using multivariate statistics. Chem. Biol. Drug Des., 2008, 72(4), 257-264.
86. Giaginis, C.; Tsantili-Kakoulidou, A.; Theocharis, S. Quantitative structure-activity relationship (QSAR) methodology in forensic toxicology: modeling postmortem redistribution of structurally diverse drugs using multivariate statistics. Forensic Sci. Int., 2009, 190(1-3), 9-15.
87. Giaginis, C.; Theocharis, S.; Tsantili-Kakoulidou, A. A QSAR study on indole-based PPAR-γ agonists in respect to receptor binding and gene transactivation data. QSAR Comb. Sci., 2009, 28(8), 802-805.
88. Oprea, T.I. Property distribution of drug-related chemical databases. J. Comput. Aided Mol. Des., 2000, 14(3), 251-264.
89. Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
90. Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
91. Muegge, I. Selection criteria for drug-like compounds. Med. Res. Rev., 2003, 23(3), 302-321.
92. Madden, J.C.; Cronin, M.T. Structure-based methods for the prediction of drug metabolism. Expert Opin. Drug Metab. Toxicol., 2006, 2(4), 545-557.
93. Zuñiga L.; Calvo, B. Global vision about the biological medicinal products: biosimilars. Curr. Pharm. Biotechnol., 2009, 10(8), 772-774.
94. Nissen-Meyer, J.; Rogne, P.; Oppegård, C.; Haugen, H.S.; Kristiansen, P.E. Structure-function relationships of the nonlanthionine-containing peptide (class II) bacteriocins produced by gram-positive bacteria. Curr. Pharm. Biotechnol., 2009, 10(1), 19-37.
95. Singh, B.K.; Dubey, V.K. In silico studies on tryparedoxin peroxidase of Leishmania infantum: structural aspects. Curr. Pharm. Biotechnol., 2009, 10(6), 626-630.
96. Martin, P.L.; Breslin, W.; Rocca, M.; Wright, D.; Cavagnaro, J. Considerations in assessing the developmental and reproductive potential of biopharmaceuticals. Birth Defects Res. B Dev. Reprod. Toxicol., 2009, 86(3), 176-203.
97. Waysbort, A.; Giroux, M.; Mansat, V.; Teixeira, M.; Dumas, J.C.; Puel, J. Experimental study of transplacental passage of alpha interferon by two assay techniques. Antimicrob. Agents Chemother., 1993, 37(6), 1232-1237.
98. Simister, N.E. Placental transport of immunoglobulin G. Vaccine, 2003, 21(24), 3365-3369.
99. Kane, S.V.; Acquah, L.A. 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(1), 228-233.
100. Malek, A.; Sager, R.; Kuhn, P.; Nicolaides, K.H.; Schneider, H. Evaluation of maternofetal transport of immunoglobulins during human pregnancy. Am. J. Reprod. Immunol., 1996, 36(5), 248-255.
101. Schneider, H.; Miller, R.K. Receptor-mediated uptake and transport of macromolecules in the human placenta. Int. J. Dev. Biol., 2010, 54(2-3), 367-375.
102. May, K.; Grube, M.; Malhotra, I.; Long, C.A.; Singh, S.; Mandaliya, K.; Siegmund, W.; Fusch, C.; Schneider, H.; King, C.L. Antibody-dependent transplacental transfer of malaria blood-stage antigen using a human ex vivo placental perfusion model. PLoS One, 2009, 4(11), e7986.
103. Malek, A.; Sager, R.; Schneider, H. Transport of proteins across the human placenta. Am. J. Reprod. Immunol., 1998, 40(5), 347-351.
104. Pentsuk, N.; van der Laan, J.W. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res. B Dev. Reprod. Toxicol., 2009, 86(4), 328-344.
105. Martin, P.L.; Zhou, Z.; Van den Bulck, K.; Kwok, D.; Powers, G.; Jiao, Q.; Schantz, A.; Treacy, G. Pharmacology and placental transfer of a human alphav integrin monoclonal antibody in rabbits. Birth Defects Res. B Dev. Reprod. Toxicol., 2010, 89(2), 116-123.
106. Bussiere, J.L.; Martin, P.; Horner, M.; Couch, J.; Flaherty, M.; Andrews, L.; Beyer, J.; Horvath, C. Alternative strategies for toxicity testing of species-specific biopharmaceuticals. Int. J. Toxicol., 2009, 28(3), 230-253.