Role of P-glycoprotein in the pharmacotherapy of pregnant women
Abstract
This review addresses the function of the protein-transporter glycoprotein-P (Pgp, ABCB1 protein) and the expression of its encoding gene MDR1/mdr1 throughout the gestational period in humans and animals. We discuss the relationship between the transporter function and the hormone fluctuations during pregnancy. We cite studies on the association between the MDR1/mdr1 gene polymorphisms and the hemato-placental barrier permeability for Pgp substrates, as well as fetal malformations. Under a separate section, drugs commonly used in pregnant women are characterized in terms of their roles as substrates, inducers or inhibitors of the Pgp transporter.
About the Authors
N. M. Popova
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Natalya M. Popova – PhD, Senior Lecturer, Department of Pharmacology with Course of Pharmacy, Faculty of Continuous Professional Education
A. V. Shchulkin
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Alexey V. Shchulkin – PhD, Associate Professor, Department of Pharmacology with Course of Pharmacy, Faculty of Continuous Professional Education
I. V. Chernykh
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Ivan V. Chernykh – PhD (Biology), Assistant, Department of General and Pharmaceutical Chemistry
A. S. Esenina
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Anna S. Esenina – Medical Student
Russian Federation
Anna S. Esenina – Medical Student
M. M. Gradinar
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Maria M. Gradinar – Medical Student
E. N. Yakusheva
Ryazan State Medical University named after Аcademician I.P. Pavlov, Health Ministry of Russian Federation
Russian Federation
Russian Federation
Elena N. Yakusheva – MD, PhD, Professor, Head of Department of Pharmacology with Course of Pharmacy, Faculty of Continuous Professional Education,
References
1. Zhuravleva E.O., Velts N.Yu., Zatolochina K.E. et al. Analysis of spontaneous reports of adverse reactions that have developed with the use of drugs during pregnancy. [Analiz spontannyh soobshchenij o nezhelatel'nyh reakciyah, razvivshihsya pri primenenii lekarstvennyh sredstv vo vremya beremennosti]. Bezopasnost' i risk farmakoterapii. 2017;5(2):61–9. (In Russ.).
2. Radzinsky V.E., Tochiev G.F. Polypragmasy in the treatment of pregnant women. [Polipragmaziya v lechenii beremennyh zhenshchin]. Farmateka. 2011;13:10–1. (In Russ.).
3. Adam M.P., Polifka J.E., Friedman J.M. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet. 2011;157(3):175–82. DOI: 10.1002/ajmg.c.30313.
4. Strizhenok E.A., Gudkov I.V., Strachunskiy L.S. The use of drugs in pregnancy: the results of a multicenter pharmacoepidemiological study. [Primenenie lekarstvennyh sredstv pri beremennosti: rezul'taty mnogocentrovogo farmakoepidemiologicheskogo issledovaniya]. Klinicheskaya mikrobiologiya i antimikrobnaya himioterapiya. 2017;9(2):162–75. (In Russ.).
5. Sher S.A. Teratogenic effects of medicines on the future child's organism at the stage of intrauterine development. [Teratogennoe vozdejstvie lekarstvennyh sredstv na organizm budushchego rebenka na etape vnutriutrobnogo razvitiya]. Pediatricheskaya farmakologiya. 2011;8(6):57–9. (In Russ.).
6. Stetsyuk O.U., Andreeva I.V. Emerging concepts in use of macrolides in pregnancy and lactation. [Primenenie makrolidov pri beremennosti i laktacii]. Klinicheskaya mikrobiologiya i antimikrobnaya himioterapiya. 2010;12(1):41–53. (In Russ.).
7. Gatsanoga M.V., Chernykh I.V., Shchulkin A.V. et al. The method of assessment of drugs belonging to the substrates of P- glycoprotein on female rabbits. [Mozhno li ocenivat' prinadlezhnost' lekarstvennyh veshchestv k substratam glikoproteina-P na samkah krolikov porody shinshilla]. Nauka molodyh (Eruditio Juvenium). 2016;(3):5–10. (In Russ.).
8. Yakusheva E.N., Chernykh I.V., Shchulkin A.V., Popova N.M. P-glycoprotein: structure, physiological role and molecular mechanisms of modulation functional activity. [Glikoprotein-P: struktura, fiziologicheskaya rol' i molekulyarnye mekhanizmy modulyacii funkcional'noj aktivnosti]. Uspekhi fiziologicheskih nauk. 2014;45(4):89–98. (In Russ.).
9. Enders A.C., Blankenship T.N. Comparative placental structure. Adv Drug Deliv Rev. 1999;38(1):3–15.
10. Zhang H., Wu X., Wang H. et al. Effect of pregnancy on cytochrome P450 3a and P-glycoprotein expression and activity in the mouse: mechanisms, tissue specificity, and time course. Mol Pharmacol. 2008;74(3):714–23.
11. Kalabis G.M., Kostaki A., Andrews M.H. et al. Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection. Biol Reprod. 2005;73:591–7.
12. Ceckova-Novotna M., Pavek P., Staud F. P-glycoprotein in the placenta: expression, localization, regulation and function. Reprod Toxicol. 2006;22(3):400–10.
13. Chung F.S., Eyall S., Muzi M. et al. Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate. Вr J Pharmacol. 2010;159:394–404.
14. Gil S., Saura R., Forestier F., Farinotti R. P-glycoprotein expression of the human placenta during pregnancy. Placenta. 2005;26:268–70.
15. Mathias A.A., Hitti J., Unadkat J.D. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am J Physiol Regul Integr Comp Physiol. 2005;289(4):R963–9.
16. Yang C.P., DePinho S.G., Greenberger L.M. et al. Progesterone interacts with P-glycoprotein in multidrug-resistant cells and in the endometrium of gravid uterus. J Biol Chem. 1989;264(2):782–8.
17. Huang Q.T., Shynlova O., Kibschull M. et al. P-glycoprotein expression and localization in the rat uterus throughout gestation and labor. Reproduction. 2016;152(3):195–204.
18. Arceci R.J., Baas F., Raponi R.et al. Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol Reprod Develop. 1990;25:101–9.
19. Popova N.M., Shchulkin A.V., Chernykh I.V. et al. P-glycoprotein functional activity in “Soviet Chinchilla” rabbits during pregnancy. [Funkcional'naya aktivnost' glikoproteina-P u krolikov porody «Sovetskaya shinshilla» pri beremennosti]. Rossijskij medikobiologicheskij vestnik im. akad. I.P. Pavlova. 2018;26(4):466–73. (In Russ.).
20. Shchulkin A.V., Chernykh I.V., Yakusheva E.N. et al. Estradiol influence on functioning of ABCB1-protein in experiment. [Vliyanie estradiola na funkcionirovanie ABCB1-belka v eksperimente]. Vestnik Ural'skoj medicinskoj akademicheskoj nauki. 2017;14(4):427–34. (In Russ.).
21. Shchulkin A.V., Chernykh I.V., Yakusheva E.N. et al. Progesterone influence on functional activity of glycoprotein-P in experiment. [Vliyanie progesterona na funkcional'nuyu aktivnost' glikoproteina-P v eksperimente]. Himiko-farmacevticheskij zhurnal. 2017;52(6):102–7. (In Russ.).
22. Shchulkin A.V., Yakusheva E.N., Chernykh I.V. et al. Testosterone influence on functional activity of glycoprotein-P. [Vliyanie testosterona na funkcional'nuyu aktivnost' glikoproteina-P]. Himiko-farmacevticheskij zhurnal. 2017;51(9):3–7. (In Russ.).
23. Lankas G.R., Wise L.D., Cartwright M.E. et al. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol. 1998;12:457–63.
24. Smit J.W., Huisman M.T., van Tellingen O. et al. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest. 1999;104:1441–7.
25. Hitzl M., Schaeffeler E., Hocher B. et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics. 2004;14:309–18.
26. Tanabe M., Ieiri I., Nagata N. et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther. 2001;297(3):1137–43.
27. Obermann-Borst S.A., Isaacs A., Younes Z. et al. General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect. Am J Obstet Gynecol. 2011;204(3):236.e1–e8.
28. Bliek B.J.B., van Schaik R.H.N., van der Heiden I.P. et al. Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with clef lip with or without cleft palate. Am J Med Genet A. 2009;149A(10):2088–92.
29. Li J., Wang Z., Chen Y.P. et al. Association of fetal but not maternal P-glycoprotein C3435T polymorphism with fetal growth and birth weight, a possible risk factor for cardiovascular diseases in later life. Clin Lab. 2012;58:1085–9.
30. Sokova E.A., Kukes V.G. The significance of ABCB1 gene C3435T polymorphism study for the evaluation of benefit/risk beta-blockers treatment in Russian pregnant women with chronic hypertension. [Znachenie izucheniya polimorfizma gena ABCB1, kodiruyushchego glikoprotein-R, dlya ocenki otnosheniya ozhidaemoj pol'zy k vozmozhnomu risku primeneniya beta-adrenoblokatorov u russkih beremennyh s hronicheskoj arterial'noj gipertenziej]. Biomedicina. 2014;(2):119–27. (In Russ.).
31. Diagnosis and treatment of cardiovascular diseases during pregnancy: Russian recommendations, 2013. [Diagnostika i lechenie serdechnososudistyh zabolevanij pri beremennosti: Rossijskie rekomendacii, 2013]. Rossijskij kardiologicheskij zhurnal. 2013;(4, prilozhenie 1): 1–40. (In Russ.). Available at: http://www.scardio.ru/content/ Guidelines/beremennie_rek_2013.pdf.
32. Kukes V.G., Grachev S.V., Sychev D.A., Ramenskaya G.V. Metabolism of drugs. The scientific basis of personalized medicine: a guideline for physicians. Moskva: GEOTAR-Media, 2008. 304 p. (In Russ.).
33. Bachmakov I., Werner U., Endress B. et al. Characterization of betaadrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol. 2006;20(3):273–82.
34. Atkinson D.E., Brice-Bennett S., D’Souza S.W. Antiepileptic medication during pregnancy: does fetal genotypeaffect outcome? Pediatric Research. 2007;62(2):120–7.
35. Meador K.J., Baker G.A., Finnell R.H. et al. In utero antiepileptic drug exposure: fetal death and malformations. Neurology. 2006;67:407–12.
36. Pennell P.B. Pregnancy in the woman with epilepsy: maternal and fetal outcomes. Semin Neurol. 2002;22:299–308.
37. Loscher W., Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2(1):86–98.
38. Didziapetris R., Japertas P., Avdeef A., Petrauskas A. Classification analysis of P-glycoprotein substrate specificity. J Drug Target. 2003;11(7):391–406.
39. Rahangdale L., Guerry S., Bauer H.M. et al. An observational cohort study of Chlamydia trachomatis treatment in pregnancy. Sex Transm Dis. 2006;33:106–10.
40. Czeizel A.E., Rockenbauer M., Sorensen H.Y., Olsen J. A populationbased case-control teratologic study of oral erythromycin treatment during pregnancy. Reprod Toxicol. 1999;13:531–6.
41. Amsden G.W. Erythromycin, clarithromycin, and azithromycin: are the differences real? Clin Ther. 1996;18:56–72.
42. Biaxin (Clarithromycin). Product Information. RxList. Internet Drug Index. Available at: http://www.rxlist.com/biaxin-drug.htm.
43. Desmonts G., Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies. New Engl J Med. 1974;50:1110–6.
44. Adamyan L.V., Afonina L.Yu., Baranov I.I. et al. The use of antiretroviral drugs in a set of measures aimed at preventing mother-to-child transmission of HIV. Clinical recommendations (treatment protocol). [Primenenie antiretrovirusnyh preparatov v komplekse mer, napravlennyh na profilaktiku peredachi VICh ot materi rebenku. Klinicheskie rekomendacii (protokol lecheniya)]. Problemy reprodukcii. 2015;21(6S):215–45. (In Russ.).
45. Huisman M.T., Smit J.W., Schinkel A.H. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS. 2000;14(3):237–42.
46. Weiss J., Weis N., Ketabi-Kiyanvash N. et al. Comparison of the induction of P-glycoprotein activity by nucleotide,nucleoside, and non-nucleoside reverse transcriptase inhibitors. Eur J Pharmacol. 2008;579:104–9.
47. Camus M., Delomenie C., Didier N. et al. Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women. Placenta. 2005;27:699–706.
48. Newell M.L. Mechanisms and timing of mother-to-child transmission of HIV-1. AIDS. 1998;12:831–7.
49. Iqbal M., Audette M.C., Petropoulos S. et al. Placental drug transporters and their role in fetal protection. Placenta. 2012:33:137–42.
Supporting agencies: The study was supported by the Russian Foundation for Вasic Research, grant № А18-015-00259.
For citation:
Popova N.M., Shchulkin A.V., Chernykh I.V., Esenina A.S., Gradinar M.M., Yakusheva E.N. Role of P-glycoprotein in the pharmacotherapy of pregnant women. Obstetrics, Gynecology and Reproduction. 2019;13(2):164-173. https://doi.org/10.17749/2313-7347.2019.13.2.164-173
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