Studies of drug absorption have most often been performed at two very different levels: the membrane/cell/intestinal segment level and the whole animal/man level. The former focuses on membrane transport while the latter focuses on simple description of absorption. The proposed research will develop the necessary understanding and test a systematic approach to utilizing and integrating the information from these two levels.
The specific aims of the proposed research are: (1) develop an approach for obtaining intestinal mucosal membrane permeabilities to obtain information more directly related to the in vivo absorption process; (2) develop and validate a physiological flow model approach to estimating human oral absorption; and (3) testing this approach in dogs and humans by conducting oral absorption studies on five drugs: cimetidine, furosemide, nadolol, mefenamic acid and propranolol. The intestinal perfusion method for estimating the intestinal wall permeability will be extended to the nonsteady-state case in order to study more variables (pH, drug concentration, solvent flux, nutrient effects) with fewer animals and to obtaining estimates of the absorption rate constant. Measurement of the gastric and intestinal fluid flows and pH will be measured in dogs and man as a function of motility state. These results will be incorporated into a micro-mixing model of the intestine and used to develop a stochastic modeling approach to predicting oral drug delivery. The approach will be tested with five drugs, cimetidine, nadolol, furosemide, mefenamic acid and propranolol which exhibit a range of drug properties: pH dependence, dissolution control, acid/base absorption and first-pass metabolism. The result of this research will fill a very significant pp in the understanding of drug absorption: connecting information at the basic membrane level with oral absorption and bioavailability in man. Estimates of human drug absorption and absorption variability can then be made on the basis of few animal experiments and used to provide more optimal drug therapy to man. The approach is based on determining the underlying fundamental mechanisms controlling drug absorption and once developed will allow estimation of oral drug absorption in disease states that effect the GI tract, leading to more optimal drug therapy of sick patients.
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