ORAL DRUG DELIVERY AND BIOAVAILABILITY--AIDS

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Drug absorption and bioavailability is largely treated on an empirical basis with after-the-fact analysis of studies in animals and/or humans. This is undoubtedly due to the complexity of processes involved in drug absorption and metabolism from the gastrointestinal tract. The proposed research project has as its long-term objective the development of a comprehensive physiologically based transport model of the gastrointestinal tract which, when combined with appropriate results of animal and human experiments on the basic underlying physiological processes, will be predictive of drug absorption in humans. When fully developed, the approach will be mechanistic and enable the prediction of mean plasma levels as well as expected intra- and intersubject variation based on the measured variation of the underlying physiological parameters, such as gastric emptying rate, intestinal transit rate, intestinal pH and permeability, in both the fasted and fed-states. the specific aims of the proposed project are: (1) develop a general macroscopic model for estimating the extent of drug absorption from the gastrointestinal tract that includes permeability, stability, enzymatic activity, solubility and dissolution rate, measure the required parameters in animal models and/or humans and compare the estimated extent and variation of absorption with the observed results for ddI, foscarnet, cimetidine, and furosemide or nadolol; (2) extend the transport model for drug dissolution into surfactant solutions to emulsions and apply this model to estimating the extend of drug absorption for water insoluble drugs in humans; (3) develop a binding, transport and physiological model for the efficacy of cholestyramine and colestipol resins, determine the appropriate in vitro measurements to correlate with in vivo efficacy and apply this pharmacodynamic model to improving the efficacy of these drug products; (4) extend the gastrointestinal hepatic physiological flow model for the systemic bioavailability variability of the beta-blocker propranolol and the NSAID ibuprofen from dogs to humans; and (5) develop a physiological micro- mixing model of the gastrointestinal tract, including transit, dissolution and drug permeation through the intestinal membrane. The model will account for intestinal permeability changes down the gastrointestinal tract as well as flow rate and luminal environment changes, i.e., pH, buffer surfactant and lipid content and enzyme concentrations. The model will also include the gastrointestinal variations associated with gastric emptying and intestinal transit in the fasted and fed-state and the phase related variations in transit and luminal content. When fully developed this mechanistic approach will allow the estimation of drug absorption and drug absorption variability in humans based on a minimum amount of basic information on the drug and dosage form. Furthermore, when fully developed, a mechanistic approach will have the further advantage of being able to predict drug absorption and plasma levels in diseased states that alter the gastrointestinal physiological variables. This will aid in more optimal treatment of sick patients, such as those with AIDS.