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Pharmacokinetics and Toxicity of Bismuth Compounds

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  • Toxicology Management Review
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Summary

Inorganic bismuth salts are poorly soluble in water: solubility is influenced by the acidity of the medium and the presence of certain compounds with (hydr)oxy or sulfhydryl groups. The analysis of bismuth in biological material is not standardised and is subject to large variation; it is difficult to compare data from different studies, and older data should be approached with caution.

The normal concentration of bismuth in blood is between 1 and 15 μg/L, but absorption from oral preparations produces a significant rise. Distribution of bismuth in the organs is largely independent of the compound administered or the route of administration: the concentration in kidney is always highest and the substance is also retained there for a long time. It is bound to a bismuth-metal binding protein in the kidney, the synthesis of which can be induced by the metal itself. Elimination from the body takes place by the urinary and faecal routes, but the exact proportion contributed by each route is still unknown. Elimination from blood displays multicompartment pharmacokinetics, the shortest half-life described in humans being 3.5 minutes, and the longest 17 to 22 years.

A number of toxic effects have been attributed to bismuth compounds in humans: nephropathy, encephalopathy, osteoarthropathy, gingivitis, stomatitis and colitis. Whether hepatitis is a side effect, however, is open to dispute. Each of these adverse effects is associated with certain bismuth compounds. Bismuth encephalopathy occurred in France as an epidemic of toxicity and was associated with the intake of inorganic salts including bismuth subnitrate, subcarbonate and subgallate. In the prodromal phase patients developed problems in walking, standing or writing, deterioration of memory, changes in behaviour, insomnia and muscle cramps, together with several psychiatric symptoms. The manifest phase started abruptly and was characterised by changes in awareness, myoclonia, astasia and/or abasia and dysarthria. Patients recovered spontaneously after discontinuation of bismuth. Intestinal lavage, forced diuresis and haemodialysis have been tried without positive effects on the clinical condition of the patient or on blood bismuth concentration, and the use of dimercaprol as an antidote has produced reports of both positive and negative findings. To confirm the diagnosis of bismuth encephalopathy, it is essential to find elevated bismuth concentrations in blood, plasma, serum or CSF. A safety level of 50 μg/L and an alarm level of 100 μg/L have been suggested in the past, but no proof is available to support the choice of these levels. The safety level will need to be reconsidered when the analysis and toxicological evaluation of bismuth have been definitively settled. In encephalopathy patients, additional pathological information can be obtained from EEG, CT scan, plain x-ray of the abdomen and postmortem investigations.

The bismuth encephalopathy occurred only in France and the surrounding countries, despite extensive use of bismuth elsewhere. A small outbreak of poisoning was also seen in Australian patients who had undergone a colostomy or an ileostomy and taken oral bismuth subgallate. A so far unidentified additional factor besides bismuth was held responsible for these intoxications. Despite many theories on enhanced intestinal absorption, the exact aetiology of bismuth encephalopathy remains a mystery.

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    Anja Slikkerveer &  Frederik A. de Wolff (Professor of Toxicology)

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Slikkerveer, A., de Wolff, F.A. Pharmacokinetics and Toxicity of Bismuth Compounds. Med Toxicol Adverse Drug Exp 4, 303–323 (1989). https://doi.org/10.1007/BF03259915

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