Актуальные представления о фармакологической коррекции железодефицитных состояний в гинекологической практике

Духанин А.С. Актуальные представления о фармакологической коррекции железодефицитных состояний в гинекологической практике. Гинекология. 2021; 23 (4): 300–306. DOI: 10.26442/20795696.2021.4.201064

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Dukhanin AS. Current views on the pharmacological correction of iron deficiency conditions in gynecological practice. Gynecology. 2021; 23 (4): 300–306. DOI: 10.26442/20795696.2021.4.201064

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Аннотация

Рассматриваются особенности фармакокинетики железа и фолиевой кислоты (ФК), которые влияют на проведение эффективной микронутритивной поддержки: молекулярные механизмы абсорбции и распределения, гомеостатические процессы сохранения плазменного уровня витаминов и минералов по механизму обратной связи, в том числе за счет регуляции депонирования. Важной характеристикой феррокинетики является наличие единственного экспортера железа – ферропортина, активность которого контролируется семейством железорегуляторных белков. Различают системную ферротерапию и пероральный способ доставки железа. В общем виде комплексы парентерального препарата железа состоят из ядра, представленного оксидом/гидроксидом Fe(III), которое стабилизируется углеводной полимерной оболочкой. После поступления в кровоток комплексы железа поглощаются резидентными макрофагами ретикулоэндотелиальной системы печени, селезенки и костного мозга. Системные формы препаратов Fe(III) представляют собой пролекарства, из которых активный фрагмент, т.е. железо, высвобождается в лизосомальном матриксе фагоцитов. Пероральные формы железа делятся на содержащие двух- и трехвалентное железо. Обсуждается влияние факторов, определяющих отличия в усвоении пероральных форм двухвалентного и трехвалентного железа, спектр нежелательных побочных эффектов, а также ключевые фармацевтические подходы для повышения переносимости и приверженности ферротерапии. К ним относятся применение препаратов на основе органических соединений Fe(II), имеющих более низкую скорость диссоциации, чем неорганические соли железа, замедление высвобождения активной фармацевтической субстанции Fe(II) из лекарственной формы. В обзоре особое внимание уделяется фолатам как синергистам железа, разбираются особенности фармакокинетики ФК, молекулярные основы синергизма, обосновывается применение комбинированных препаратов железа и ФК.

Ключевые слова: микронутриенты, феррокинетика, системная ферротерапия, пероральные формы железа, фолиевая кислота, синергизм, комбинированные препараты

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The review considers features of iron and folic acid (FA) pharmacokinetics, which affect the effective micronutrient support: molecular mechanisms of absorption and distribution, homeostatic processes of maintaining plasma vitamin and mineral levels by the feedback mechanism, including by regulating the deposition. An important characteristic of ferrokinetics is the presence of unique iron exporter ferroportin which is controlled by a family of iron regulatory proteins. Systemic ferrotherapy and oral rout of iron delivery are distinguished. In general, parenteral iron preparation complexes consist of Fe(III) oxide/hydroxide core stabilized by a carbohydrate polymer shell. Once entering the bloodstream, iron complexes are absorbed by resident macrophages of the reticuloendothelial system of the liver, spleen and bone marrow. Systemic
Fe(III) preparations are prodrugs, the active part of which, i.e. iron is released in the lysosomal matrix of phagocytes. Oral iron preparations are divided into those containing bivalent (ferrous) and trivalent (ferric) iron. The article discusses factors determining the differences in the absorption of oral ferrous and ferric iron preparation, the spectrum of side effects, as well as key pharmaceutical approaches to increase the tolerance and adherence of ferrotherapy. These include using preparations containing Fe(II) organic compounds that have a lower dissociation rate than inorganic iron salts as well as slowing down the release of the active Fe(II) pharmaceutical substance from the drug. The review pays special attention to folates as iron synergists and examines the features of FA pharmacokinetics, the molecular basis of synergism, and substantiates the use of combined iron and FA preparations.

Key words: micronutrients, ferrokinetics, systemic ferrotherapy, oral iron preparations, folic acid, synergism, combined preparations

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Список литературы

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________________________________________________

1. Borel P, Desmarchelier C. Bioavailability of Fat-Soluble Vitamins and Phytochemicals in Humans: Effects of Genetic Variation. Annu Rev Nutr. 2018;38:69-96.
DOI:10.1146/annurev-nutr-082117-051628
2. Gromova OA, Torshin IIu, Tetruashvili NK, Gogoleva IV. Sistematicheskii analiz farmakologicheskikh svoistv protein suktsinilata zheleza. Effektivnaia farmakoterapiia. 2018;13:20-9 (in Russian).
3. Bhandari S, Pereira DIA, Chappell HF, Drakesmith H. Intravenous Irons: From Basic Science to Clinical Practice. Pharmaceuticals. 2018;11(82):2-20.
4. Knutson MD. Iron-sensing proteins that regulate hepcidin and enteric iron absorption. Annu Rev Nutr. 2010;30:149-71. DOI:10.1146/annurev.nutr.012809.104801
5. Camaschella C. Iron-Deficiency Anemia. N Engl J Med. 2015;372:1832-43.
6. Gammella E, Buratti P, Cairo G, Recalcati S. Macrophages: central regulators of iron balance. Metallomics. 2014;6(8):1336-45. DOI:10.1039/c4mt00104d
7. Koskenkorva-Frank TS, Weiss G, Koppenol WH, Burckhardt S. The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. Free Radic Biol Med. 2013;65:1174-94.
8. Anderson GJ, Wang F. Essential but toxic: controlling the ﬂux of iron in the body. Clin Exp Pharmacol Physiol. 2012;39:719-24.
9. Martin-Malo A, Borchard G, Flühmann B, et al. Differences between intravenous iron products: focus on treatment of iron deﬁciency in chronic heart failure patients. ESC Heart Failure. 2019;6:241-53. DOI:10.1002/ehf2.12400
10. Auerbach M, Macdougall I. The available intravenous iron formulations: History, efﬁcacy, and toxicology. Hemodial Int. 2017;21(Suppl. 1):S83-92. DOI:10.1111/hdi.12560
11. Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3(1):12-33. DOI:10.3390/pharmaceutics3010012
12. Neiser S, Rentsch D, Dippon U, et al. Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. Biometals. 2015;28(4):615-35. DOI:10.1007/s10534-015-9845-9
13. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004;15 (Suppl. 2):S93-8. DOI:10.1097/01.ASN.0000143814.49713.C5
14. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24-38.
15. DeLoughery TG. Safety of Oral and Intravenous Iron. Acta Haematol. 2019;142(1):8-12.
16. Nielsen P, Gabbe EE, Fischer R, Heinrich HC. Bioavailability of iron from oral ferric polymaltose in humans. Arzneimittelforschung. 1994;44(6):743-8.
17. Pereira DI, Irving СSS, Lomer MC, Powell JJ. A rapid, simple questionnaire to assess gastrointestinal symptoms after oral ferrous sulphate supplementation. BMC Gastroenterol. 2014;14:103.
18. Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview. Scientific World Journal. 2012;2012:846824.
19. Lane DJ, Bae DH, Merlot AM, et al. Duodenal cytochrome b (DCYTB) in iron metabolism: an update on function and regulation. Nutrients. 2015;7(4):2274-96.
20. Maret W. The metals in the biological periodic system of the elements: concepts and conjectures. Int J Mol Sci. 2016;17:66.
21. Chen P, Chakraborty S, Mukhopadhyay S, et al. Manganese homeostasis in the nervous system. J Neurochem. 2015;134(4):601-10. DOI:10.1111/jnc.13170
22. Binding, Transport and Storage of Metal Ions in Biological Cells. Ed. W Maret, AG Wedd. Cambridge: Royal Society of Chemistry, 2014.
23. Wu W, Song Y, He C, et al. Divalent metal-ion transporter 1 is decreased in intestinal epithelial cells and contributes to the anemia in inflammatory bowel disease. Sci Rep. 2015;5:16344. DOI:10.1038/srep16344
24. Juarez-Vazquez J, Bonizzoni E, Scotti A. Iron plus folate is more effective than iron alone in the treatment of iron deficiency anaemia in pregnancy: a randomised, double blind clinical trial. BJOG. 2002;109(9):1009-14. DOI:10.1111/j.1471-0528.2002.01378.x
25. Koury MJ. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron. Annu Rev Nutr. 2004;24:105-31. DOI:10.1146/annurev.nutr.24.012003.132306
26. Siekmans K, Roche M, Kung'u JK, et al. Barriers and enablers for iron folic acid (IFA) supplementation in pregnant women. Matern Child Nutr. 2018;14(S5):e12532.
27. Suliburska J, Chmurzynska A, Kocylowski R, et al. Effect of Iron and Folic Acid Supplementation on the Level of Essential and Toxic Elements in Young Women. Int JEnviron Res Public Health. 2021;18(3):1360. DOI:10.3390/ijerph18031360
28. Keats EC, Haider BA, Tam E, Bhutta ZA. Multiple-micronutrient supplementation for women during pregnancy. Cochrane Database Syst Rev. 2019;3:CD004905.
29. Torshin IIu, Gromova OA, Limanova OA, et al. A meta-analysis of clinical studies on the use of iron fumarate for the prevention and treatment of iron deficiency anemia in pregnant women. Gynecology. 2015;17(5):24-31 (in Russian).
30. Radziejewska A, Suliburska J, Kołodziejski P, Chmurzynska A. Simultaneous supplementation with iron and folic acid can affect Slc11a2 and Slc46a1 transcription and metabolite concentrations in rats. Br J Nutr. 2020;123(3):264-72. DOI:10.1017/S0007114519002721
31. Gyimesi G, Pujol-Giménez J, Kanai Y, Hediger MA. Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application. Pflugers Arch. 2020;472(9):1177-206. DOI:10.1007/s00424-020-02433-x
32. Said HM, Nexo E. Gastrointestinal Handling of Water-Soluble Vitamins. Compr Physiol. 2018;8(4):1291-311. DOI:10.1002/cphy.c170054
33. Zeckanovic A, Kavcic M, Prelog T, et al. Micronized, Microencapsulated Ferric Iron Supplementation in the Form of >Your< Iron Syrup Improves Hemoglobin and Ferritin Levels in Iron-Deficient Children: Double-Blind, Randomized Clinical Study of Efficacy and Safety. Nutrients. 2021;13(4):108.
34. Geisser P, Burckhardt S. The Pharmacokinetics and Pharmacodynamics of Iron Preparations. Pharmaceutics. 2011;3(1):12-33.
35. Dukhanin AS. Criteria for the responsible selection of vitamin and mineral complex for pregravid preparation, pregnancy and lactation: clinical pharmacological and pharmaceutical aspects. Rus. med. zhurn. 2017;2:109-15 (in Russian).
36. Alekseev KV, Blynskaia EV, Siziakov C, et al. Vspomogatel'nye veshchestva v tekhnologii tverdykh kapsul. Farmatsiia. 2009;5:31-6 (in Russian).
37. Shikh EV. Biodostupnost' peroral'nykh preparatov. Rus. med. zhurn. 2007;15(2):95-9 (in Russian).
38. Gromova OA, Torshin IYu. Micronutrients and Reproductive Health. Management. Moscow: GEOTAR-Media, 2019 (in Russian).
39. Markl D, Zeitler JA. A Review of Disintegration Mechanisms and Measurement Techniques. Pharm Res. 2017;34(5):890-917. DOI:10.1007/s11095-017-2129-z

Авторы

А.С. Духанин*

ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
*das03@rambler.ru

________________________________________________

Aleksandr S. Dukhanin*

Pirogov Russian National Research Medical University, Moscow, Russia
*

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