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Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats

  • Karin Weisser
  • Thomas Göen
  • Jennifer D. Oduro
  • Gaby Wangorsch
  • Kay-Martin O. Hanschmann
  • Brigitte Keller-Stanislawski
Inorganic Compounds
  • 67 Downloads

Abstract

Knowledge of dose linearity, plasma clearance, rate and extent of subcutaneous (SC) and intramuscular (IM) absorption of soluble aluminium (Al) citrate is considered a prerequisite for evaluation of toxicokinetic data obtained from SC or IM administration of Al adjuvants in medicinal products. Therefore, total Al plasma kinetics was investigated after SC, IM, and IV administration of single Al doses (36 and 360 µg/kg IM or SC; 30 and 300 µg/kg IV) given as citrate solution in rats. Control groups receiving vehicle (saline) were run in parallel to monitor background plasma Al levels over time resulting from dietary intake. Evaluation of Al plasma profiles was done by both non-compartmental analysis of baseline-corrected data and simultaneous model fitting to the raw data using a population kinetics approach. High and dose-independent total plasma clearance (6.6 mL/min/kg) was observed after IV administration corresponding to 60–82% of normal rat GFR. This supports the previous assumptions that parenterally administered Al citrate is more rapidly cleared from plasma than other Al species (e.g., chloride or lactate). Furthermore, plasma exposure of Al (Cmax and AUC0–inf) increased dose-proportionally at all administration routes. Fast and complete absorption of Al was observed at each dose level after both SC and IM administration (bioavailability estimates: 88 and 110%). Estimates for the first-order absorption rate constant ka correspond to absorption half-lives of 36 min (SC) and ≤ 13 min (IM). There was no increase in tissue Al content (whole bone and brain) after 36 µg/kg IM compared to control rats.

Keywords

Aluminium Aluminium citrate Toxicokinetics Rat Intramuscular administration Subcutaneous administration 

Notes

Acknowledgements

The authors thank Barbara Verhoeven for her technical assistance and Daniela Golomb for preparation of the treatment formulations.

Funding

The project was funded by the German Ministry of Health (ZMVI1-2515-FSB-772).

Compliance with ethical standards

Conflict of interest

Author Jennifer D. Oduro declares that she is employee at preclinics GmbH, a contract research organisation that has received payment for the conductance of the animal study. All the other authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution (preclinics GmbH, Germany) at which the studies were conducted.

Supplementary material

204_2018_2323_MOESM1_ESM.docx (6 kb)
Supplementary material 1 (DOCX 6 KB)
204_2018_2323_MOESM2_ESM.docx (4 kb)
Supplementary material 2 (DOCX 4 KB)

References

  1. DeVoto E, Yokel RA (1994) The biological speciation and toxicokinetics of aluminum. Environ Health Perspect 102:940–951CrossRefGoogle Scholar
  2. Fifield K (1997) Study of the kinetics of al absorption and excretion in humans. Department of Nuclear Physics. Annual Report. Australian National University Canberra, pp 97–99Google Scholar
  3. Flarend RE, Hem SL, White JL, Elmore D, Suckow MA, Rudy AC, Dandashli EA (1997) In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine 15:1314–1318CrossRefGoogle Scholar
  4. Fleischer M, Schaller KH (1999) Aluminium—determination in plasma. In: Angerer J, Schaller KH (eds) Analyses of hazardous substances in biological materials, vol 6. Wiley, WeinheimGoogle Scholar
  5. Giusti F, Seubert A, Cantisani R, Tortoli M, D’Oro U, Ferlenghi I, Dallai R, Piccioli D (2015) Ultrastructural visualization of vaccine adjuvant uptake in vitro and in vivo. Microsci Microanal 21:791–795CrossRefGoogle Scholar
  6. Göen T, Schaller KH, Drexler H (2012) External quality assessment of human biomonitoring in the range of environmental exposure levels. Int J Hyg Environ Health 215:229–232CrossRefGoogle Scholar
  7. Hirayama M, Iijima S, Iwashita M, Akiyama S, Takaku Y, Yamazaki M, Omori T, Yumoto S, Shimamura T (2011) Aging effects of major and trace elements in rat bones and their mutual correlations. J Trace Elem Med Biol 25:73–84CrossRefGoogle Scholar
  8. Lin WT, Chen RC, Lu WW, Liu SH, Yang FY (2015) Protective effects of low-intensity pulsed ultrasound on aluminum-induced cerebral damage in Alzheimer’s disease rat model. Sci Rep 5:9671CrossRefGoogle Scholar
  9. Lote CJ, Wood JA, Saunders HC (1992a) Renal filtration, reabsorption and excretion of aluminium in the rat. Clin Sci (Lond) 82:13–18CrossRefGoogle Scholar
  10. Lote CJ, Saunders HC, Wood JA, Spencer AJ (1992b) Effect of citrate on plasma aluminium concentration and aluminium excretion in the rat. Clin Sci (Lond) 83:431–435CrossRefGoogle Scholar
  11. Lote CJ, Willmott K, Wood JA, Thewles A, Freeman M (1995) Renal excretion of aluminium in the rat: effect of citrate infusion. Hum Exp Toxicol 14:945–948CrossRefGoogle Scholar
  12. Meirav O, Sutton RA, Fink D, Middleton R, Klein J, Walker VR, Halabe A, Vetterli D, Johnson RR (1991) Accelerator mass spectrometry: application to study of aluminium kinetics in the rat. Am J Physiol 260:F466–F469PubMedGoogle Scholar
  13. Michalke B, Halbach S, Nischwitz V (2009) JEM spotlight: metal speciation related to neurotoxicity in humans. J Environ Monit 11:939–954CrossRefGoogle Scholar
  14. Morefield GL, Sokolovska A, Jiang D, HogenEsch H, Robinson JP, Hem SL (2005) Role of aluminum-containing adjuvants in antigen internalization by dendritic cells in vitro. Vaccine 23:1588–1595CrossRefGoogle Scholar
  15. Nolte E, Beck E, Winklhofer C, Steinhausen C (2001) Compartmental model for aluminium biokinetics. Hum Exp Toxicol 20:111–117CrossRefGoogle Scholar
  16. O’Flaherty EJ (1991) Physiologically based models for bone-seeking elements. I. Rat skeletal and bone growth. Toxicol Appl Pharmacol 111(2):299–312CrossRefGoogle Scholar
  17. Öhman LO, Martin RB (1994) Citrate as the main small molecule binding Al3+ in serum. Clin Chem 40:598–601PubMedGoogle Scholar
  18. Pai SM, Melethil S (1989) Kinetics of aluminum in rats I: dose-dependent elimination from blood after intravenous administration. J Pharm Sci 3:200–202CrossRefGoogle Scholar
  19. Poirier J, Semple H, Davies J, Lapointe R, Dziwenka M, Hiltz M, Mujibi D (2011) Double-blind, vehicle-controlled randomized twelve-month neurodevelopmental toxicity study of common aluminum salts in the rat. Neuroscience 193:338–362CrossRefGoogle Scholar
  20. Priest ND (2004) The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J Environ Monit 6:375–403CrossRefGoogle Scholar
  21. Priest ND, Newton D, Day JP, Talbot RJ, Warner AJ (1995) Human metabolism of aluminium-26 and gallium-67 injected as citrates. Hum Exp Toxicol 14:287–293CrossRefGoogle Scholar
  22. Probst M, Kühn JP, Scheuch E, Seidlitz A, Hadlich S, Evert K, Oswald S, Siegmund W, Weitschies W (2016) Simultaneous magnetic resonance imaging and pharmacokinetic analysis of intramuscular depots. J Control Release 227:1–12CrossRefGoogle Scholar
  23. Rowland M, Tozer TN (2011) Clinical pharmacokinetics and pharmacodynamics: concepts and applications, 4th edn. Wolters Kluwer/Lippincott Williams and Wilkins, BaltimoreGoogle Scholar
  24. Shirley DG, Lote CJ (2005) Renal handling of aluminium. Nephron Physiol 101:99–103CrossRefGoogle Scholar
  25. Shirley DG, Walter MF, Walter SJ, Thewles A, Lote CJ (2004) Renal aluminium handling in the rat: a micropuncture assessment. Clin Sci (Lond) 107:159–165CrossRefGoogle Scholar
  26. Spencer AJ, Wood JA, Saunders HC, Freeman MS, Lote CJ (1995) Aluminium deposition in liver and kidney following acute intravenous administration of aluminium chloride or citrate in conscious rats. Hum Exp Toxicol 14(10):787–794CrossRefGoogle Scholar
  27. Steinhausen C (1997) Untersuchung der Aluminiumbiokinetik mit 26Al und Beschleunigermassenspektrometrie. Dissertation, Technical University of Munich, GermanyGoogle Scholar
  28. Talbot RJ, Newton D, Priest ND, Austin JG, Day JP (1995) Inter-subject variability on the metabolism of aluminium follwing intravenous injection as citrate. Hum Exp Toxicol 14:595–599CrossRefGoogle Scholar
  29. Veiga M, Bohrer D, Banderó CR, Oliveira SM, do Nascimento PC, Mattiazzi P, Mello CF, Lenz QF, Oliveira MS (2013) Accumulation, elimination, and effects of parenteral exposure to aluminum in newborn and adult rats. J Inorg Biochem 128:215–220CrossRefGoogle Scholar
  30. Verdier F, Burnett R, Michelet-Habchi C, Moretto P, Fievet-Groyne F, Sauzeat E (2005) Aluminium assay and evaluation of the local reaction at several time points after intramuscular administration of aluminium containing vaccines in the Cynomolgus monkey. Vaccine 23:1359–1367CrossRefGoogle Scholar
  31. Weisser K, Stübler S, Matheis W, Huisinga W (2017) Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products. Regul Toxicol Pharmacol 88:310–321CrossRefGoogle Scholar
  32. Wilhelm M, Zhang XJ, Hafner D, Ohnesorge FK (1992) Single-dose toxicokinetics of aluminum in the rat. Arch Toxicol 66:700–705CrossRefGoogle Scholar
  33. Willhite CC, Karyakina NA, Yokel RA, Yenugadhati N, Wisniewski TM, Arnold IM, Momoli F, Krewski D (2014) Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Crit Rev Toxicol 44(Suppl. 4):1–80CrossRefGoogle Scholar
  34. Xu ZX, Pai SM, Melethil S (1991) Kinetics of aluminum in rats. II: dose-dependent urinary and biliary excretion. J Pharm Sci 10:946–951CrossRefGoogle Scholar
  35. Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics: an updated minireview. Pharmacol Toxicol 88:159–167CrossRefGoogle Scholar
  36. Yokel RA, Rhineheimer SS, Sharma P, Elmore D, McNamara P (2001) Entry, half-life, and desferrioxamine-accelerated clearance of brain aluminum after a single (26)Al exposure. Toxicol Sci 64:77–82CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines)LangenGermany
  2. 2.Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-Alexander-Universität Erlangen-NürnbergErlangenGermany
  3. 3.Preclinics GmbHPotsdamGermany

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