Colonic metabolism of ranitidine: implications for its delivery and absorption

The aim of this study was to assess the in vitro stability of ranitidine to colonic bacteria by utilising a batch culture fermentation system to simul ate the conditions of the colon. Three quantities of ranitidine, 100, 200 a nd 500 mg, in the form of the hydrochloride salt, were introduced into indi vidual 100 ml fermenters consisting of buffer medium inoculated with freshl y voided human faeces (10% w/v). Control experiments were also run in paral lel using equivalent drug quantities in buffer medium without the presence of faeces. Samples were removed at pre-determined time intervals over a 24 h period and were subsequently analysed by high-performance liquid chromato graphy (HPLC) for drug concentration. A selection of the samples removed fr om the fermenters was also analysed by conventional UV spectroscopy and mas s spectrometry. Subsequent to an initial dissolution phase in the fermentat ion system, a marked decline in ranitidine concentration was noted over tim e, thereby suggesting degradation and metabolism of the drug by colonic bac teria, No such decline in concentration was noted in the control buffer sys tems. The rate and extent of metabolism was rapid and complete within 12 an d 24 h for the 100 mg and 200 mg samples, respectively, although the larges t sample size, 500 mg, was only partly metabolised over the course of the e xperiment. UV and mass spectrometry analysis indicated that metabolism occu rred via cleavage of an N-oxide bond within the molecule with the resultant loss of an oxygen atom, although further metabolic reactions are possible. Such metabolism may in part be responsible for the poor bioavailability of ranitidine from the colon. (C) 2001 Elsevier Science B.V. All rights reser ved.