INTESTINAL ABSORPTION/METABOLISM OF H2 ANTAGONISTS

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This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. The long-term objective of the proposed research is to determine the influence of intestinal metabolism on the oral availability of histamine- receptor2 (H2) antagonists. In preliminary studies, substantial appearance of the sulfoxide metabolite was observed in the intestinal lumen from jejunal but not ileal perfusion of cimetidine in rats. Furthermore appearance of metabolite in rat jejunum was blocked by a mucosal anion exchange inhibitor. Cimetidine sulfoxide was also observed in two human jejunal perfusions but to a lesser extent than in rats. The four commercially-available H2-antagonists (cimetidine, ranitidine, famotidine and nizatidine) are among the most frequently prescribed legend drugs. Their oral bioavailabilities differ significantly but double plasma level peaks are characteristic of all four drugs. Hepatic sulfoxidation profiles also differ and it has been postulated that diminished clearance of sulfoxide metabolites contribute to the central nervous system toxicity of this class of agents. Intestinal metabolism and metabolite export may constitute a significant mode of elimination for the H2-antagonists that has not been previously uncovered. The site- specific nature of intestinal clearance may account for double-peaking and metabolic differences may account for bioavailability differences. Drug and species differences in intestinal metabolism will be investigated in rat and human perfusion studies. Intestinal reduction of sulfoxide metabolite, possible systemic clearance via the intestine and fed-state effects on intestinal clearance will be studied in rat perfusions. Metabolism kinetics will be studied in intestinal cell suspensions and kinetics and directionality of drug and metabolite transport will be investigated in Ussing chambers using both intestinal tissue and Caco-2 cell monolayers. Studies to uncouple cellular metabolism from metabolite export kinetics will be performed with cimetidine sulfoxide-loaded brush border membrane vesicles. Drug intestinal permeability and metabolite data obtained from human perfusion studies will be incorporated in a physiologic model utilizing existing information on renal and hepatic clearance to project the impact of intestinal metabolism and absorption variability on drug and metabolite plasma levels. Mechanistic details from the more isolated studies will be utilized to refine model parameters obtained from perfusions. Intestinal metabolism/export of xenobiotics is an area of investigation that has received little attention. It is the goal of this research proposal to expand this knowledge base in animal and human studies with a group of agents enjoying extensive clinical utility. If H2-antagonist intestinal metabolism and/or export prove to have a significant impact on drug plasma level variability, the tools developed in this study will be used to explore the intestinal metabolism of other drug classes. The biochemical mechanisms underlying these preliminary in situ observations may have more general implications for the GI tract as an organ of drug elimination.