Biological Trace Element Research

, Volume 153, Issue 1–3, pp 243–250 | Cite as

Effects of Dietary Factors on the Pharmacokinetics of 58Fe-labeled Hemin After Oral Administration in Normal Rats and the Iron-deficient Rats

  • Yongjie Zhang
  • Di Zhao
  • Jie Xu
  • Chunxiang Xu
  • Can Dong
  • Qingwang Liu
  • Shuhua Deng
  • Jie Zhao
  • Wei Zhang
  • Xijing Chen


Hemin, iron (III) protoporphyrin chloride (IX), as a stable form of heme iron, has been used in iron absorption studies. The aim of the present study was to elucidate the influences of body iron status and three dietary factors (green tea extract, ascorbic acid, and calcium) on the pharmacokinetics of hemin using stable isotope labeling methods followed by ICP-MS measurement. In this study, a rapid, sensitive, and specific ICP-MS method for the determination of 58Fe originating from hemin in rat plasma was developed and a rat model of iron deficiency anemia was established. It was found that hemin iron absorption increased significantly under iron deficiency anemia status, with AUC0−t and AUC0–∞ showing significant increase in anemic rats compared to normal ones. Green tea extract strongly inhibited hemin iron absorption in both normal rats and iron-deficient rats. In normal rats administered with green tea extract, C max resulted significantly reduced, whereas in anemic rats administered with green tea extract both AUC0−t and AUC0–∞ were reduced. On the other hand, ascorbic acid significantly affected hemin iron absorption only in iron-deficient rats, in which C max showed a significant increase. Interestingly, calcium slowed down the hemin iron absorption rate in normal rats, MRT0–t being significantly different in calcium-treated animals compared to untreated ones. This trend also appeared in the iron-deficient group but it did not reach statistical significance. Our data suggest that the mechanism of hemin iron absorption is regulated by body iron status and dietary factors can influence hemin iron absorption to varying degrees. Moreover, these results may also have general implication in the iron deficiency treatment with iron supplements and fortification of foods.


Fe Hemin Iron-deficient rats Iron absorption Pharmacokinetics Dietary factors ICP-MS 



Inductively coupled plasma mass spectrometry


Area under concentration–time curve


Maximum plasma concentration




Apparent volume of distribution


Half life time


Mean retention time


Erythrocyte count






Red cell distribution width


Mean corpuscular volume


Mean corpuscular hemoglobin


Mean corpuscular hemoglobin concentration


Serum iron


Total iron-binding capacity


Transferrin saturation


Serum ferritin




Heme carrier protein 1


Divalent metal transporter 1



The study was supported by Jiangsu Province Nanjing City Innovative Graduate Research Program (No. CXLL11_0814) and Jiangsu Province Promotion Foundation for the Key Lab of Drug Metabolism and Pharmacokinetics (No. BM2012012).


  1. 1.
    Killip S, Bennett JM, Chambers MD (2007) Iron deficiency anemia. Am Fam Physician 75:671–678PubMedGoogle Scholar
  2. 2.
    Davidsson L, Dimitriou T, Boy E, Walczyk T, Hurrell RF (2002) Iron bioavailability from iron-fortified Guatemalan meals based on corn tortillas and black bean paste. Am J Clin Nutr 75:535–539PubMedGoogle Scholar
  3. 3.
    Davidsson L, Walczyk T, Zavaleta N, Hurrell RF (2001) Improving iron absorption from a Peruvian school breakfast meal by adding ascorbic acid or Na2EDTA. Am J Clin Nutr 73:283–287PubMedGoogle Scholar
  4. 4.
    Pizarro F, Olivares M, Hertrampf E, Nuñez S, Tapia M, Cori H, de Romana DL (2006) Ascorbyl palmitate enhances iron bioavailability in iron-fortified bread. Am J Clin Nutr 84:830–834PubMedGoogle Scholar
  5. 5.
    Reddy MB, Hurrell RF, Cook JD (2000) Estimation of nonheme-iron bioavailability from meal composition. Am J Clin Nutr 74:937–943Google Scholar
  6. 6.
    Kim EY, Ham SK, Shigenaga MK, Han O (2008) Bioactive dietary polyphenolic compounds reduce nonheme iron transport across human intestinal cell monolayers. J Nutr 138:1647–1651PubMedGoogle Scholar
  7. 7.
    Cook JD, Reddy MB (2001) Effects of ascorbic acid intake on nonheme-iron absorption from a complete diet. Am J Clin Nutr 73:93–98PubMedGoogle Scholar
  8. 8.
    Miret S, Tascioglu S, Van Der Burg M, Frenken L, Klaffke W (2010) In vitro bioavailability of iron from the heme analogue sodium iron chlorophyllin. J Agric Food Chem 58:1327–1332PubMedCrossRefGoogle Scholar
  9. 9.
    Tenhunen R, Tokola O, Linden IB (1987) Haem arginate: a new stable haem compound. J Pharm Pharmacol 39:780–786PubMedCrossRefGoogle Scholar
  10. 10.
    Siegert SW, Holt RJ (2008) Physicochemical properties, pharmacokinetics, and pharmacodynamics of intravenous hematin: a literature review. Adv Ther 25:842–857PubMedCrossRefGoogle Scholar
  11. 11.
    Laftah AH, Raja KB, Beaumont N, Simpson RJ, Deacon A, Solanky N, Srai SK, Peters TJ (2004) The effects of inhibition of haem biosynthesis by griseofulvin on intestinal iron absorption. Basic Clin Pharmacol Toxicol 94:161–168PubMedGoogle Scholar
  12. 12.
    Masaratana P, Laftah AH, Latunde-Dada GO, Vaulont S, Simpson RJ, McKie AT (2011) Iron absorption in hepcidin1 knockout mice. Br J Nutr 105:1583–1591PubMedCrossRefGoogle Scholar
  13. 13.
    Kalgaonkar S, Lönnerdal B (2008) Effects of dietary factors on iron uptake from ferritin in Caco-2 cells. J Nutr Biochem 19:33–39PubMedCrossRefGoogle Scholar
  14. 14.
    Fidler MC, Davidsson L, Zeder C, Hurrell RF (2004) Erythorbic acid is a potent enhancer of nonheme-iron absorption. Am J Clin Nutr 79:99–102PubMedGoogle Scholar
  15. 15.
    Fiorito V, Crich SG, Silengo L, Altruda F, Aime S, Tolosano E (2011) Assessment of iron absorption in mice by ICP-MS measurements of 57Fe levels. Eur J Nutr 51:783–789PubMedCrossRefGoogle Scholar
  16. 16.
    Zhao D, Zhang Y, Xu C, Dong C, Lin H, Zhang L, Li C, Ren S, Wang X, Yang S, Han D, Chen X (2012) Pharmacokinetics, tissue distribution, and plasma protein binding study of platinum originating from dicycloplatin, a novel antitumor supramolecule, in rats and dogs by ICP-MS. Biol Trace Elem Res 148:03–208Google Scholar
  17. 17.
    Raffin SB, Woo CH, Roost KT, Price DC, Schmid R (1974) Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest 54:1344–1352PubMedCrossRefGoogle Scholar
  18. 18.
    Bjorn-Rasmussen E (1983) Iron absorption: present knowledge and controversies. Lancet 1:914–916PubMedCrossRefGoogle Scholar
  19. 19.
    Proulx AK, Reddy MB (2006) Iron bioavailability of hemoglobin from soy root nodules using a Caco-2 cell culture model. J Agric Food Chem 54:518–1522CrossRefGoogle Scholar
  20. 20.
    Reeves PG (1997) Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr 127:838S–841SPubMedGoogle Scholar
  21. 21.
    Akase T, Onodera S, Matsushita R, Akase T, Tashiro S (2004) A comparative study of laboratory parameters and symptoms effected by Toki-shakuyaku-san and an iron preparation in rats with iron-deficiency anemia. Biol Pharm Bull 27:871–878PubMedCrossRefGoogle Scholar
  22. 22.
    Fu J, Yang A, Ma Y, Liu M, Zhang L, Wang Y, Liu L (2011) The effect of fetal and early postnatal iron deficiency on iron metabolism in adult rats. Biol Trace Elem Res 149:412–418CrossRefGoogle Scholar
  23. 23.
    Kumara VM, Wessling-Resnick M (2012) Olfactory ferric and ferrous iron absorption in iron-deficient rats. Am J Physiol Lung Cell Mol Physiol 302:L1280–L1286CrossRefGoogle Scholar
  24. 24.
    Roberts SK, Henderson RW, Young GP (1993) Modulation of uptake of heme by rat small intestinal mucosa in iron deficiency. Am J Physiol 265:G712–G718PubMedGoogle Scholar
  25. 25.
    West AR, Oates PS (2008) Mechanisms of heme iron absorption: Current questions and controversies. World J Gastroenterol 14:4101–4110PubMedCrossRefGoogle Scholar
  26. 26.
    Sakakibara S, Aoyama Y (2002) Dietary iron-deficiency up-regulates hephaestin mRNA level in small intestine of rats. Life Sci 70:3123–3129PubMedCrossRefGoogle Scholar
  27. 27.
    Hurrell R, Egli I (2010) Iron bioavailability and dietary reference values. Am J Clin Nutr 91:1461S–1467SPubMedCrossRefGoogle Scholar
  28. 28.
    Hallberg L, Rossander-Hulthen L, Brune M, Gleerup A (1993) Inhibition of haem-iron absorption in man by calcium. Br J Nutr 69:533–540PubMedCrossRefGoogle Scholar
  29. 29.
    Ma Q, Kim EY, Lindsay EA, Han O (2011) Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner in human intestinal caco-2 cells. J Food Sci 76:H143–H150PubMedCrossRefGoogle Scholar
  30. 30.
    Villarroel P, Flores S, Pizarro F, de Romaña DL, Arredondo M (2011) Effect of dietary protein on heme iron uptake by Caco-2 cells. Eur J Nutr 50:637–643PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Yongjie Zhang
    • 1
  • Di Zhao
    • 1
  • Jie Xu
    • 1
  • Chunxiang Xu
    • 2
  • Can Dong
    • 2
  • Qingwang Liu
    • 3
  • Shuhua Deng
    • 1
  • Jie Zhao
    • 1
  • Wei Zhang
    • 1
  • Xijing Chen
    • 1
  1. 1.Center of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjingPeople’s Republic of China
  2. 2.Jiangsu Product Quality Test & Inspect InstituteNanjingPeople’s Republic of China
  3. 3.State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjingPeople’s Republic of China

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