Split Daily Oral Iron Dosing Enhances Correction of Iron-Deficiency Anemia in Rats
Mohamed M. El-Kady
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorCorresponding Author
Nermeen Bastawy
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorMohamed Amin
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorSoha Elmorsy
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorOlfat Shaker
Department of Medical Biochemistry and Molecular Biology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorAbeer Mostafa
Department of Medical Biochemistry and Molecular Biology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorEman Hassan Nadwa
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Department of Pharmacology and Therapeutics , College of Medicine , Jouf University , Sakaka , Saudi Arabia , ju.edu.sa
Search for more papers by this authorMarwa Abdel-Rahman
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorMohamed M. El-Kady
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorCorresponding Author
Nermeen Bastawy
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorMohamed Amin
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorSoha Elmorsy
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorOlfat Shaker
Department of Medical Biochemistry and Molecular Biology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorAbeer Mostafa
Department of Medical Biochemistry and Molecular Biology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorEman Hassan Nadwa
Department of Medical Pharmacology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Department of Pharmacology and Therapeutics , College of Medicine , Jouf University , Sakaka , Saudi Arabia , ju.edu.sa
Search for more papers by this authorMarwa Abdel-Rahman
Department of Medical Physiology , Faculty of Medicine , Cairo University , Cairo , Egypt , cu.edu.eg
Search for more papers by this authorAbstract
Iron deficiency is the leading cause of anemia worldwide. Single oral iron daily supplementation is usually unsatisfactory. We hypothesize dividing the oral iron dose may improve the anemic parameters. To test this hypothesis, forty male Wistar rats were evenly assigned to the following groups (n = 8): Control nonanemic or anemic groups. Anemia was induced by repeated phlebotomy from the orbital plexus under anesthesia for 4 weeks. The anemic rats either received no treatment (IDA group) or received a total oral iron supplementation (7.1 mg/kg/day) for 1 week. Iron was administered in different treatment regimens: single dose per day (IDA-Fe-sid group), twice per day (IDA-Fe-bid group), or thrice per day (IDA-Fe-tid group). The hemoglobin concentration, hematocrit values, total iron-binding capacity (TIBC), and serum levels of iron, ferritin, and hepcidin were measured to assess the anemia. The results showed that administration of iron in divided doses for 1 week exerted significant restorative effects on the measured anemia parameters, unlike the single daily regimen. In conclusion: oral iron supplementation in divided doses increased the oral iron bioavailability; therefore, it may be more efficient in improving the anemia parameters than a single dose in short-term treatment of IDA. In clinical practice, dividing the total large iron dose into multiple smaller doses may correct IDA more quickly, especially in patients who cannot tolerate a single large dose.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
Filename | Description |
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anem9976840-sup-0001-f1.jpgJPEG image, 147.3 KB | Supporting Information 1 Supporting figure graphic abstract: Schematic representation of the study design illustrating the four anemic groups subjected to biweekly phlebotomy over 4 weeks to induce iron deficiency anemia: nontreated iron-deficient group (IDA) and three treatment groups receiving daily oral iron once (IDA-Fe-sid), twice (IDA-Fe-bid), or three times (IDA-Fe-tid). At the end of the study, blood samples were collected for the assessment of hemoglobin (Hb), hematocrit, serum iron, total iron-binding capacity (TIBC), serum ferritin, and hepcidin levels. |
anem9976840-sup-0002-f2.pdfPDF document, 60.3 KB | Supporting Information 2 Supporting table: Raw data of the anemia parameters: hemoglobin (Hb), hematocrit, serum iron, total iron-binding capacity (TIBC), serum ferritin, and hepcidin levels. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Kassebaum N. J., Jasrasaria R., Naghavi M. et al., A Systematic Analysis of Global Anemia Burden from 1990 to 2010, Blood. (2014) 123, no. 5, 615–624, https://doi.org/10.1182/blood-2013-06-508325, 2-s2.0-84894067309.
- 2
Higgins P. D. R. and
Rockey D. C., Iron-deficiency Anemia, Techniques in Gastrointestinal Endoscopy. (2003) 5, no. 3, 134–141, https://doi.org/10.1053/j.tgie.2003.08.002, 2-s2.0-0345874633.
10.1053/j.tgie.2003.08.002 Google Scholar
- 3 Rana S. and Prabhakar N., Iron Disorders and Hepcidin, Clinica Chimica Acta. (2021) 523, 454–468, https://doi.org/10.1016/j.cca.2021.10.032.
- 4 Camaschella C., Iron Deficiency, Blood. (2019) 133, no. 1, 30–39, https://doi.org/10.1182/blood-2018-05-815944, 2-s2.0-85059448775.
- 5 Cao G., Wang Y., Wu Y., Jing W., Liu J., and Liu M., Prevalence of Anemia Among People Living with HIV: A Systematic Review and Meta-Analysis, eClinicalMedicine. (2022) 44, https://doi.org/10.1016/j.eclinm.2022.101283.
- 6 Pasricha S.-R. S., Flecknoe-Brown S. C., Allen K. J. et al., Diagnosis and Management of Iron Deficiency Anaemia: a Clinical Update, Medical Journal of Australia. (2010) 193, no. 9, 525–532, https://doi.org/10.5694/j.1326-5377.2010.tb04038.x.
- 7 Johnson-Wimbley T. D. and Graham D. Y., Diagnosis and Management of Iron Deficiency Anemia in the 21st Century, Therapeutic Advances in Gastroenterology. (2011) 4, no. 3, 177–184, https://doi.org/10.1177/1756283X11398736, 2-s2.0-80052308801.
- 8 Percy L., Mansour D., and Fraser I., Iron Deficiency and Iron Deficiency Anaemia in Women, Best Practice & Research Clinical Obstetrics & Gynaecology. (2017) 40, 55–67, https://doi.org/10.1016/j.bpobgyn.2016.09.007, 2-s2.0-85005980713.
- 9 Fuqua B. K., Vulpe C. D., and Anderson G. J., Intestinal Iron Absorption, Journal of Trace Elements in Medicine & Biology. (2012) 26, no. 2-3, 115–119, https://doi.org/10.1016/j.jtemb.2012.03.015, 2-s2.0-84862583029.
- 10 Tuleu C., Andrieux C., Boy P., and Chaumeil J. C., Gastrointestinal Transit of Pellets in Rats: Effect of Size and Density, International Journal of Pharmaceutics. (1999) 180, no. 1, 123–131, https://doi.org/10.1016/S0378-5173(98)00400-1, 2-s2.0-0033034920.
- 11 Andrews N. C., Disorders of Iron Metabolism, New England Journal of Medicine. (1999) 341, no. 26, 1986–1995, https://doi.org/10.1056/NEJM199912233412607, 2-s2.0-0033599057.
- 12 Zimmermann M. B. and Hurrell R. F., Nutritional Iron Deficiency, Lancet. (2007) 370, no. 9586, 511–520, https://doi.org/10.1016/S0140-6736(07)61235-5, 2-s2.0-34547652466.
- 13 Kwong R. W. M., Andrés J. A., and Niyogi S., Molecular Evidence and Physiological Characterization of Iron Absorption in Isolated Enterocytes of Rainbow Trout (Oncorhynchus mykiss): Implications for Dietary Cadmium and Lead Absorption, Aquatic Toxicology. (2010) 99, no. 3, 343–350, https://doi.org/10.1016/j.aquatox.2010.05.012, 2-s2.0-77955551976.
- 14 Shi X.-Q., Zhu Z.-H., Yue S.-J. et al., Integration of Organ Metabolomics and Proteomics in Exploring the Blood Enriching Mechanism of Danggui Buxue Decoction in Hemorrhagic Anemia Rats, Journal of Ethnopharmacology. (2020) 261, https://doi.org/10.1016/j.jep.2020.113000.
- 15 Urso K., Leal Martínez-Bujanda J., and del Prado J. M., Iron Protein Succinylate in the Management of Iron Deficiency Anemia: A Comparative Study with Ferrous Sulphate at Low and High Therapeutic Doses, Nutrients. (2021) 13, no. 3, https://doi.org/10.3390/nu13030968.
- 16 Nair A. B. and Jacob S., A Simple Practice Guide for Dose Conversion between Animals and Human, Journal of Basic and Clinical Pharmacy. (2016) 7, no. 2, 27–31, https://doi.org/10.4103/0976-0105.177703.
- 17
Urso K.,
Leal Martínez-Bujanda J., and
del Prado J. M., Iron Protein Succinylate in the Management of Iron Deficiency Anemia: A Comparative Study with Ferrous Sulphate at Low and High Therapeutic Doses, 2021, https://doi.org/10.3390/nu13030968.
10.3390/nu13030968 Google Scholar
- 18 Krishna K. M., Gopal G. S., Chalam C. R. V. et al., The Influence of Sulindac on Diabetic Cardiomyopathy: A Non-invasive Evaluation by Doppler Echocardiography in Streptozotocin-Induced Diabetic Rats, Vascular Pharmacology. (2005) 43, no. 2, 91–100, https://doi.org/10.1016/j.vph.2005.02.012, 2-s2.0-22144468699.
- 19 Agoston D. V., How to Translate Time? the Temporal Aspect of Human and Rodent Biology, Frontiers in Neurology. (2017) 8, https://doi.org/10.3389/fneur.2017.00092, 2-s2.0-85016151688.
- 20 Youdim M. B. H., Green A. R., Bloomfield M. R., Mitchell B. D., Heal D. J., and Grahame-Smith D. G., The Effects of Iron Deficiency on Brain Biogenic Monoamine Biochemistry and Function in Rats, Neuropharmacology. (1980) 19, no. 3, 259–267, https://doi.org/10.1016/0028-3908(80)90148-3, 2-s2.0-0018875855.
- 21 Tang N., Chen L. Q., and Zhuang H., Effects of Heme Iron Enriched Peptide on Iron Deficiency Anemia in Rats, Food & Function. (2014) 5, no. 2, 390–399, https://doi.org/10.1039/C3FO60292C, 2-s2.0-84893310010.
- 22 Zou H., Banerjee P., Leung S. S. Y., and Yan X., Application of Pharmacokinetic-Pharmacodynamic Modeling in Drug Delivery: Development and Challenges, Frontiers in Pharmacology. (2020) 11, no. 997, https://doi.org/10.3389/fphar.2020.00997.
- 23 Lledó-García R., Nácher A., Prats-García L., Casabó V. G., and Merino-Sanjuán M., Bioavailability and Pharmacokinetic Model for Ritonavir in the Rat, Journal of Pharmaceutical Sciences. (2007) 96, no. 3, 633–643, https://doi.org/10.1002/jps.20683, 2-s2.0-33947547028.
- 24 Pergola P. E. and Kopyt N. P., Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients with CKD: A Randomized Trial and Open-Label Extension, American Journal of Kidney Diseases. (2021) 78, no. 6, 846–856.e1, https://doi.org/10.1053/j.ajkd.2021.03.020.
- 25 Stoffel N. U., Cercamondi C. I., Brittenham G. et al., Iron Absorption from Oral Iron Supplements Given on Consecutive versus Alternate Days and as Single Morning Doses versus Twice-Daily Split Dosing in Iron-Depleted Women: Two Open-Label, Randomised Controlled Trials, The Lancet. Haematology. (2017) 4, no. 11, e524–e533, https://doi.org/10.1016/s2352-3026(17)30182-5, 2-s2.0-85030768193.
- 26 Moretti D., Goede J. S., Zeder C. et al., Oral Iron Supplements Increase Hepcidin and Decrease Iron Absorption from Daily or Twice-Daily Doses in Iron-Depleted Young Women, Blood. (2015) 126, no. 17, 1981–1989, https://doi.org/10.1182/blood-2015-05-642223, 2-s2.0-84944736888.
- 27 von Siebenthal H. K., Gessler S., Vallelian F. et al., Alternate Day versus Consecutive Day Oral Iron Supplementation in Iron-Depleted Women: a Randomized Double-Blind Placebo-Controlled Study, eClinicalMedicine. (2023) 65, https://doi.org/10.1016/j.eclinm.2023.102286.
- 28 Bulbul A., Araujo Mino E., Dake V., Bautista A., Lentkowski L., and Khorsand-Sahbaie M., Alternate Day Oral Iron Dosing in Iron Deficiency Anemia, Blood. (2018) 132, no. S1, https://doi.org/10.1182/blood-2018-99-112341.
- 29
Stanworth S. J.,
Churchill D.,
Sweity S. et al., The Impact of Different Doses of Oral Iron Supplementation during Pregnancy: a Pilot Randomized Trial, 2024, 5683–5694, https://doi.org/10.1182/bloodadvances.2024013408.
10.1182/bloodadvances.2024013408 Google Scholar
- 30 Abdullahi H., Adaji J., Isah A., Agida E., and Otu T., Daily versus Twice Daily Dose of Ferrous Sulphate Supplementation in Pregnant Women: A Randomized Clinical Trial, Nigerian Journal of Clinical Practice. (2019) 22, no. 8, 1132–1139, https://doi.org/10.4103/njcp.njcp_211_18, 2-s2.0-85070980898.
- 31 Lam M. C., Khandakar B., Heon I. et al., Daily versus Alternate-Day Iron Supplementation for Pregnant Women with Iron Deficiency Anemia: A Randomized Controlled Trial, American Journal of Perinatology. (2025) 42, no. 06, 699–707, https://doi.org/10.1055/a-2405-1381.
- 32 Nemeth E., Tuttle M. S., Powelson J. et al., Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing its Internalization, Science (New York, N.Y.). (2004) 306, no. 5704, 2090–2093, https://doi.org/10.1126/science.1104742, 2-s2.0-10844258104.
- 33 Ganz T., Erythropoietic Regulators of Iron Metabolism, Free Radical Biology and Medicine. (2019) 133, 69–74, https://doi.org/10.1016/j.freeradbiomed.2018.07.003, 2-s2.0-85049606210.
- 34 Kautz L., Jung G., Valore E. V., Rivella S., Nemeth E., and Ganz T., Identification of Erythroferrone as an Erythroid Regulator of Iron Metabolism, Nature Genetics. (2014) 46, no. 7, 678–684, https://doi.org/10.1038/ng.2996, 2-s2.0-84903578007.
- 35 Kautz L., Jung G., Du X. et al., Erythroferrone Contributes to Hepcidin Suppression and Iron Overload in a Mouse Model of β-thalassemia, Blood. (2015) 126, no. 17, 2031–2037, https://doi.org/10.1182/blood-2015-07-658419, 2-s2.0-84944930727.
- 36 Mandal U. K., Chatterjee B., and Senjoti F. G., Gastro-retentive Drug Delivery Systems and Their In Vivo Success: A Recent Update, Asian Journal of Pharmaceutical Sciences. (2016) 11, no. 5, 575–584, https://doi.org/10.1016/j.ajps.2016.04.007, 2-s2.0-84984807028.
- 37 Boldhane S. P. and Kuchekar B. S., Gastroretentive Drug Delivery of Metformin Hydrochloride: Formulation and In Vitro Evaluation Using 3(2) Full Factorial Design, Current Drug Delivery. (2009) 6, no. 5, 477–485, https://doi.org/10.2174/156720109789941641, 2-s2.0-72149087666.
- 38 Falagas M. E., Karagiannis A. K., Nakouti T., and Tansarli G. S., Compliance with Once-Daily versus Twice or Thrice-Daily Administration of Antibiotic Regimens: a Meta-Analysis of Randomized Controlled Trials, PLoS One. (2015) 10, no. 1, https://doi.org/10.1371/journal.pone.0116207, 2-s2.0-84920366839.