Distribution of bismuth in the rat after oral dosing with ranitidine bismuth citrate and bismuth subcitrate

Abstract

Bismuth preparations are used world-wide for the management of peptic ulcer disease, for eradication of Helicobacter pylori, and in the prevention and treatment of diarrhoea. However neurological toxicity of bismuth has always been a major concern and evidence has been found of the absorption of bismuth. Recent studies have suggested that the absorption of bismuth increases when bismuth salts are used with ranitidine hydrochloride. The absorption and deposition of bismuth as a result of the use of the new drug ranitidine bismuth citrate have not been yet clarified. After 15 days of twice daily oral gavage with bismuth subcitrate, 13.7 mg kg(-1) day(-1) to eight rats, deposition of bismuth was found in all the tissues studied, especially the kidney (30.81 +/- 8.59 microg g(-1) dry weight). A similar pattern of distribution and tissue concentrations was found when bismuth subcitrate was given with ranitidine hydrochloride 8.6 mg kg(-1) day(-1) to another eight rats, although this combination resulted in lower brain levels (3.12 + 1.31 microg g(-1) dry weight) than after administration of bismuth subcitrate alone (4.77 +/- 0.97 microg g(-1) dry weight). When six rats were given ranitidine bismuth citrate by gavage at 22.8 mg kg(-1) day(-1) for 15 days, kidney levels were lower (4.24 +/- 1.75 microg g(-1) dry weight) and brain levels were below detection limits; the bismuth concentrations in the faeces from this group were also significantly lower (1603 +/- 104.0 microg g(-1) dry weight) than for the two other groups. After dosing with bismuth alone or in association with ranitidine hydrochloride, bismuth was detected in several organs and deposition was not influenced by gastric pH. Blood levels correlate poorly with organ deposition and brain deposition was not always associated with encephalopathy. After administration of ranitidine bismuth citrate, significantly lower concentrations of bismuth were found in the kidney and bismuth was not detectable in the brain, suggesting lower bismuth absorption. This was confirmed by higher levels in the faeces after dosing with ranitidine bismuth citrate. Thirty days after dosing with ranitidine bismuth citrate or bismuth subcitrate, bismuth could not be detected in any of the organs examined but could be found in the urine. In conclusion, bismuth was deposited in the kidney, brain, lung and liver of rats after oral dosing with bismuth subcitrate. After oral dosing with an equivalent amount of bismuth in the form of ranitidine bismuth citrate, significantly lower concentrations of bismuth were deposited in the kidney; in the brain bismuth was not detectable.