Determination of Trimethylbismuth in the Human Body after Ingestion of Colloidal Bismuth Subcitrate

Abstract

ABSTRACT:Biological methylation and hydride formation of metals and metalloids are ubiquitous environmental processes that can lead to the formation of chemical species with significantly increased mobility and toxicity. Whereas much is known about the interaction of metal(loid)s with microorganisms in environmental settings, little information has been gathered on respective processes inside the human body as yet. Here, we studied the biotransformation and excretion of bismuth after ingestion of colloidal bismuth subcitrate (215 mg of bismuth) to 20 male human volunteers. Bismuth absorption in the stomach and upper intestine was very low, as evidenced by the small quantity of bismuth eliminated via the renal route. Total bismuth concentrations in blood increased rapidly in the first hour after ingestion. Most of the ingested bismuth was excreted via feces during the study period. Trace levels of the metabolite trimethylbismuth [(CH 3 ) 3 Bi] were detected via low temperaturegas chromatography/inductively coupled plasma-mass spectrometry in blood samples and in exhaled air samples. Concentrations were in the range of up to 2.50 pg/ml (blood) and 0.8 to 458 ng/m 3 (exhaled air), with high interindividual variation being observed. Elimination routes of bismuth were exhaled air (up to 0.03‰), urine (0.03-1.2%), and feces. The site of (CH 3 ) 3 Bi production could not be identified in the present study, but the intestinal microflora seems to be involved in this biotransformation if accompanying ex vivo studies are taken into consideration.It is a well known fact that the toxicity of metal(loid)s is essentially dependent on the chemical form, i.e., on the species of the element in question (Craig, 2003;Dopp et al., 2004; Hirner and Emons, 2004). In particular, alkylation often seems to considerably increase the toxic potential of metal(loid)s. Many studies have shown that in the environment methylated and also, in some cases, hydride species can be formed by different mechanisms and from a variety of metal(loid)s (Craig, 2003). In particular, microorganisms, e.g., bacteria and fungi, have been reported to be involved in this specific kind of conversion (Thayer, 2002).In contrast to the considerable knowledge that has accumulated on the interaction of microorganisms with metal(loid)s in the environment, a paucity of information is currently available on the respective processes inside the human body. This lack of knowledge is particularly striking in view of the fact that certain segments of the digestive tract, namely, the oral cavity and the colon, are colonized by myriads of bacteria. The difficulty of analyzing metal(loid) organic compounds at trace and even ultratrace levels might at least partly account for this information gap.After a pilot study with three volunteers , we performed an ingestion experiment with bismuth, administering this element as a single p.o. dose to 20 male volunteers in the form of a therapeutically used colloidal bismuth subcitrate compound. Bismuth was chosen as the element of interest ...

From {Bi22O26} to Chiral Ligand‐Protected {Bi38O45}‐Based Bismuth Oxido Clusters

“…[1][2][3][4][5] Although biomethylation in the human body has been reported to occur to a low extent after oral uptake of bismuth subsalicylate (BSS, Pepto Bismol), [6,7] strongly adverse side effects were neither reported for BSS nor for bismuth subcitrate (CBS, DeNol). [8][9][10] It is well known that both compounds are products of partial hydrolysis of the respective bismuth carboxylates, [11] but their composition and medicinal effect are still poorly understood.…”

“…[20] It is constructed from a central building block containing 38 bismuth and 45 oxygen atoms with three different coordination modes, m 3 , m 4 , and m 6 . The m 6 -coordinated oxygen atom is located close to the center of the cluster and might be regarded as the midpoint of a [Bi 6 O 9 ] unit, in which the triangular faces of the Bi 6 octahedron are capped by eight oxygen atoms (Figure 1 b). The six bismuth atoms of the central Bi 6 octahedron are coordinated exclusively by O 2À ligands, whereas the other bismuth atoms are additionally coordinated by oxygen atoms from salicylate ligands, DMSO, or OH À ligands.…”

CHAPTER 17. Arsenic, Antimony and Bismuth

“…In a second study, Boertz et al administered 215 mg colloidal bismuth subcitrate orally to 20 male volunteers and reported measurable amounts of the methylation product trimethylbismuth in the circulation (2.50 pg ml -1 ) and in exhaled air samples (0.8-458 ng m -3 ). 256 In a double trial of the bismuthprotein complex and an antacid preparation (Bicitropeptide s ) in 43 patients, blood and urine bismuth levels increased from a baseline of 2-11 ng l -1 and 2-29 ng l -1 respectively to ''saturation levels'' of 5-20 ng l -1 and 63-780 ng l -1 within 6 weeks without obvious evidence of toxicity. 257 No details of the diet are provided in this study and it is not known whether free Bi(III) ion was chelated or otherwise bound by dietary proteins or fibre, as is the case with many other metals.…”

Biotransformation of metal(loid)s by intestinal microorganisms

“…Although relative conversion rates are low, the ability of TMBi to migrate through the body could be an approach to explain the cases of encephalopathy diagnosed in the 1970s in French and Australian patients [111]. Noteworthy, the studies on Bi show a large interindividual variability in the metabolic potency of the intestinal microbiota [82], which has also been observed in various studies aiming at the intestinal biotransformation of pharmaceuticals [8].…”

“…In a follow-up study with 20 male human volunteers administered the same dose of CBS, the uptake, metabolism, and excretion of Bi was investigated [82]. Total Bi concentrations in blood increased rapidly in the first hour following ingestion, but overall Bi absorption in the stomach and upper intestine was very low, as evidenced by the small quantity (0.03-1.2 %) of Bi eliminated via the renal route.…”