Chelation of bismuth by combining desferrioxamine and deferiprone in rats

Abstract

Consumption and production of bismuth compounds are increasing, however, a little information on the toxic effect and also the effective method in removal of bismuth compounds are available. The present research aimed to characterize the potential efficiency of two chelators after bismuth administration for 55 days following two dose levels of 20 and 40 mg/kg body weight daily to male rats. However, we found abnormalities after bismuth administration in clinical signs, such as body weight, kidneys and liver damages, a black line on gums and skin reactions. Furthermore, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing bismuth from the body was considered. Along this line, two known chelators deferiprone (1, 2-dimethy1-3-hydroxypyride-4-one, L₁) and desferrioxamine (DFO) were chosen and tested in the acute rat model. Chelators were given orally (L₁) or intraperitoneally (DFO) as a single or combined therapy for the period of a week. Doses of L₁ and DFO were 110 mg/kg body weight in experiments. Bismuth and iron concentrations in various tissues were determined by graphite furnace and flame atomic absorption spectrometry, respectively. The combined chelation therapy results show that DFO and L₁ are able to remove bismuth ions from the body, whereas iron concentration returned to the normal level and symptoms are also decreased. DFO was more effective than L1 in reducing bismuth concentration in tissues. The efficiency of DFO + L₁ is more than DFO or L₁ in removing bismuth from organs. Our results are indicative that the design procedure might be useful for preliminary in-vivo testing of the efficiency of chelating agents. Results of combined chelators’ treatment should be confirmed in a different experimental model before extrapolation to other systems. This testing procedure of course does not provide all the relevant answers for efficiency of chelating agents in bismuth toxicity.

Keywords

bismuth bismuth chelators bismuth rats chelation deferiprone desferrioxamine iron

Get full access to this article

View all access options for this article.

References

Barman Balfour JA Foster RH (1999) Deferiprone: a review of its clinical potential in iron overload in β-thalassemia major and other transfusion-dependant diseases. Drugs 58: 553–578.

Berdoukas V Bentlev P Frost H Schnebli HP (1993) Toxicity of oral iron chelator L1. Lancet 341: 1088–1093.

Bosque MA Domingo JL Corbella J (1995) Assessment of the developmental toxicity of desferrioxamine in mice. Arch Toxicol 69: 871–872.

Clarke ET Martell AE (1992) Stabilities of 1,2-dimethyl-3-hydroxypyrid-4-one chelates of divalent and trivalent metal ions. Inorg Chim Acta 19: 57–63.

Dill K McGown EL (1994) The biochemistry of arsenic, bismuth and antimony. In: S Patai (ed), The Chemistry of Arsenic, Antimony and Bismuth Compounds. New York, NY: John Wiley and Sons, pp. 695–713.

Flora SJS Bhattacharyan R Vijayaraghavan R (1995) Combined therapeutic potential of meso-dimercaptosuccinic acid and calcium edentate on the mobilization and distribution of lead in experimental lead intoxication in rats. Fundam Appl Toxicol 25: 233–240.

Franchini M Gandini G de Gironcoli M Vassanelli A Borgna-Pignatti C Aprili G (2000) Safety and efficacy of subcutaneous bolus injection of desferroxamine in adult patients with iron overload. Blood 5: 2776–2779.

Gomez W Esparza JL Domingo JL Singha PK Jones MM (1988) Comparative aluminium mobilizing action of desferrioxamine and four 3-hydroxypyrid-4-ones in aluminium-loaded rats. Toxicology 130: 175–181.

Gomez W Esparza JL Domingo JL Singha PK Corbella J Jones MM (1988) Aluminum distribution and excretion: a comparative study of a number of chelating agent in rats. Pharmacol Toxicol 82: 295–300.

10.

Hershko C Link G Konun AM Ioav CZ (2005) Objectives and mechanism of iron chelation therapy. Ann N Y Acad Sci 1054: 124–135.

11.

Hershko C (2002) Role of iron chelation therapy in thalassemia major. Turk J Haematol 19: 121–126.

12.

Kontoghiorghes GJ (1995) New concepts of iron and aluminium chelation therapy with orally L1 (deferiprone) and other chelators. Analyst 120: 845–851.

13.

Kontoghiorghes GJ Sheppard L (1987) Simple synthesis of the potent chelators l-alkyl-3-hydroxy-2-mehylpyrid-4-ones. Inorg Chim Acta 136: 111–112.

14.

Kontoghiorghes GJ Aldouri MA Sheppard L Hoffbrand AV (1987) 1, 2 Dimethyl-3-hydroxyprid-4-one an orally activechelator for treatment of iron overload. Lancet 1: 1294–1295.

15.

Kostial K Piasek M Blanusa M Schonwald N Jones MM Singh PK (1996) Combined treatment with a new biscarbodithioate C9G2DTC and BGDTC for mobilizing cadmium deposits in rats. J Appl Toxicol 16: 157–158.

16.

Kostial K Restek-samarzija K Blanusa B Piasek M jones, MM, Singh, PK (1997) Combined oral treatment with racemic and meso-2,3 dimercaptosuccinic acid for removal of mercury in rats. Pharmacol Toxicol 81: 242–244.

17.

Slikkerveer A de Wolff FA (1989) Pharmacokinetics and toxicity of bismuth compounds. Med Toxicol Adverse Drug Exp 4: 303–323.