Basit, Abdul Waseh; (1999) The in vivo assessment of drug absorption from different regions of the human gastrointestinal tract. Doctoral thesis (Ph.D.342), University College London (United Kingdom).

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Abstract

The primary objective of the study was to develop an approach utilising conventional pharmaceutical technology as a means of assessing regional gastrointestinal drug absorption in humans. Pellets containing ranitidine as a model drug were produced by the process of extrusion-spheronisation, and subsequently characterised according to a series of physico-mechanical criteria. The initial pellet formulations were found to be inherently unstable. This problem was overcome by reducing the level of microcrystalline cellulose and water in the formulation. The resultant stable pellets were film-coated with either polyvinyl acetate phthalate or mixtures of amylose and ethylcellulose for the purpose of effecting site-specific drug release within the small intestine and colon, respectively. The colon coatings were varied in terms of thickness and ratio of amylose to ethylcellulose until the desired in vitro dissolution profiles were achieved under simulated gastrointestinal conditions. Under simulated colonic conditions, however, ranitidine was found to undergo extensive metabolism by bacterial enzymes; a phenomenon also noted with the pharmacologically related compound nizatidine, but not famotidine or cimetidine. The most promising ranitidine formulations, including the uncoated version and an intravenous preparation for control purposes, were taken forward and evaluated in ten, healthy male volunteers using simultaneous gamma scintigraphy and pharmacokinetic analysis. In addition, polyethylene glycol 400 was co-administered to establish its usefulness as an absorption marker for ranitidine and other such compounds. The uncoated, polyvinyl acetate phthalate and amylose-ethylcellulose coated pellets successfully targeted ranitidine release within the stomach, small intestine and colon, respectively. The absorption of ranitidine was found to be significantly greater from the upper regions of the gastrointestinal tract than the colon. No apparent relationship was observed between the absorption of ranitidine and polyethylene glycol 400. Polyethylene glycol 400, however, was found to significantly reduce the liquid transit time through the small intestine and also the extent of ranitidine absorption. Overall, the study confirms that such an approach offers a practical means of studying drug absorption from different regions of the human gastrointestinal tract.

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