YANG Nan, MAO ZongWan and SUN HongZhe et al., at the Department of Chemistry, University of Hong Kong and Sun Yat-sen University have characterized a series of bismuth citrate complexes by X-ray crystallography and modeled the structure of ranitidine bismuth citrate, a medicine used widely for the treatment of peptic ulcer and gastric reflux disease. The polymeric framework of bismuth citrate may serve as a "drug carrier" for delivery of other drugs in the human body. This significant contribution is reported in SCIENCE CHINA Chemistry 2010, 53(10).
Elements that possess anti-bacterial activity have significant medical applications. Bismuth, the heaviest stable element in the periodic table, exhibits anti-bacterial activity against Helicobacter pylori (H. pylori) with minimal toxicity. It is used widely to treat peptic ulcers and gastrointestinal diseases. Ranitidine bismuth citrate (RBC) is a bismuth citrate-based (Bi(cit)-based) drug, developed in 1991. It exhibits efficacy in first-, second- and third-line H. pylori infection therapies when used in combination with other antibiotics, and is more effective than proton pump inhibitor-based (PPI-based) therapy. Because of the importance of Bi(cit)-based drugs, enormous efforts have been made to elucidate their structures. However, there are few structures that reflect the nature of Bi(cit)-based drugs in the stomach.
In this work, the frameworks of four Bi(cit)-based complexes, obtained under acidic conditions to mimic conditions in the stomach, were resolved. A structural model of RBC was proposed based on the crystal structure of one of these frameworks. The decomposition behavior of Bi(cit)-based complexes in aqueous solution was investigated using ESI-MS.
Bi(cit)-based complexes form polymeric porous frameworks with bismuth citrate dimeric units ([Bi(cit)2Bi]2-) forming the skeleton. Since citrate anions in the frameworks are present in the fully deprotonated, tetraanionic form ([C6H4O7]4–), and coordinate with Bi3+ cations, the excess negative charges in these polyanionic frameworks must be balanced by further cations such as K+, [NH4]+, [H3NCH2CH2NH3]2+ or [C5H6N]+. This allows Bi(cit)-based complexes to encapsulate low-molecular mass molecules or ions, either by a diffusion process or via electrostatic interactions, similar to the "uptake process" of cations and small molecules by zeolites. Ranitidine cations were modeled into a simulated structure based on one experimental framework, revealing hydrogen-bond formation between ranitidine molecules and the citrate tetraanions. ESI-MS data indicated that the Bi(cit)-based frameworks degrade from high molecular weight polymers to low molecular weight species in acidic solution.
This paper reports a series of structures of Bi(cit)-based complexes in acidic solution (mimicking the acidic environment of the stomach), establishes an in silico model of a widely used anti-ulcer drug (ranitidine bismuth citrate), and uses experimental ESI-MS data to propose a possible metabolic fate for Bi(cit)-based drugs under the acidic conditions found in the stomach.
This work was supported by the Research Grants Council of Hong Kong (HKU 703808P, HKU 704909P, HKU 107C and HKU 75209), the National Natural Science Foundation of China and Livzon Pharmaceutical Ltd.
See the article: Yang N, Mao Z W, Sun H Z et al. Polymeric architectures of bismuth citrate based on dimeric building blocks. Sci China Chem, 2010, 53: 2152-2158, doi: 10.1007/s11426-010-4113-x
DOI: 10.1007/s11434-010-9975-y
Journal
Science China Chemistry