Most drugs are passively absorbed orally with the fraction of the dose absorbed depending on dose, solubility, pKa, partition coefficient, etc. However, drugs or prodrugs which are analogs of amino acids or small peptides may be absorbed utilizing the intestinal mucosal cell enzymes/carriers responsible for protein digestion and absorption. Recent studies suggest that Alpha-methyldopa and several Beta-lactam antibiotics are absorbed in a nonpassive (carrier mediated) manner. The first component of the proposed research is to investigate the oral absorption of Beta-lactam antibiotics which are analogs of tripeptides. For the Beta-lactam antibiotics, passive permeability and carrier parameters will be determined and structure/property absorption relationships inferred. The experimental method and data analysis is based on a new method of analyzing intestinal perfusion studies with both Michaelis-Menten and passive permeability components to membrane transport. The second component of the proposed research is to develop a prodrug strategy for improving the fraction dose absorbed of Alpha-methyldopa. The strategy based on known GI luminal, brush border and cytosol enzyme specificity and the di/tripeptide carrier system. Seventeen selected peptides will be synthesized and evaluated in the rat model. The experimental system will employ both intestinal perfusions for determination of permeability parameters and portal vein cannulation to measure bioconversion back to parent drug. Competitive inhibitor studies will be employed in both studies to substantiate the nonpassive/carrier component. While the proposed studies utilize two different therapeutic classes, the oral delivery of these agents have a common mechanistic basis. The long term object of the proposed research is to develop a systematic understanding of the gastrointestinal mucosal cell enzymes and carriers that function in protein digestion/absorption and to use this knowledge to improve the delivery of drugs which are analogs of amino acids or small peptides.
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