The elderly population currently accounts for one-quarter of prescription and over-the-counter drug sales in the U.S.A. Many aspects of physiology change as a result of the aging process and, as a result, absorption, distribution, metabolism and elimination of many drugs is also changed. The long-term goal of this work is to develop a quanitative understanding of drug absorption in the elderly. The ability to predict for which drugs there is likely to be altered response in the elderly will facilitate the optimal selection of drugs, drug doses, dosing regimens and formulations for this important patient population. Through changes in distribution, metabolism and elimination with aging have been extensively studied, changes in drug absorption received little attention. The current proposal focuses on a specific aspect of absorption, the influence of gastrointestinal (GI) pH. Literature evidence and preliminary studies indicate that the GI pH is significantly affected by aging. The effects of aging on GI pH will be determined by comparing GI pH profiles in elderly with those of young subjects. Pre- and postprandial pH response in the stomach and small intestine will be measured using a radiotelemetric technique. Comparison of the absorption of dipyridamole in elderly with normal and elevated gastric pH will be used to establish the ability to predict changes in the rate and extent of drug absorption associated with the decline in gastric acid production which occurs in a significant proportion of the elderly. The elderly GI pH profiles will be incorporated into an established model for GI drug absorption to predict the effects of aging on the absorption of a range of drugs and dosage forms. The effects of dosing regimen and inter- individual variation in absorption in the elderly population will also be predicted. In the long term, changes in other aspects of physiology such as surface area and motility will also have to be accounted for to build a comprehensive and quantitative understanding of how the absorption process changes with aging. Application of this understanding to the selection and design of appropriate drugs and dosage forms will lead to significant improvements in drug therapy for the elderly.
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