The elderly are the most medicated segment of society. Lack of a coherent data base for aged patients makes rational drug use highly uncertain. Multiple diseases and multiple medications combined with an increased sensitivity to drugs render the elderly particularly vulnerable to drug toxicity. The long-term goal of this proposal is to evaluate the affects of aging, combined with chronic ethanol, on glucuronidation, sulfation, inorganic sulfate formation and excretion. Recent effort is mostly focusing on the role of aging in oxidative metabolism. Sulfate and glucuronide conjugation can control the fraction of a drug, such as acetaminophen, that is converted to a toxic metabolite. Factors that influence these parallel, competing conjugation reactions, remain largely unexplored. Chronic exposure to ethanol, in addition to severely altering human physiology, can affect drug action and toxicity by 1) causing secondary changes in the perfusion and metabolic/excretory functions of eliminating organs; 2) increasing target organ susceptibility to toxic agents; and 3) changing drug distribution to modify the usual serum concentration versus time pattern. These issues will be explored in rats of various ages fed a diet containing ethanol as 36% of total calories. The physiologic and biochemical changes of the type seen in man will be evaluated in the rat. The pharmacokinetics of the model phenolic drug acetaminophen and of sulfate anion will be compared in control and ethanol fed- rats of ages 5, 15 and 25 months. In vivo alterations will be correlated with in vitro enzyme activities and acetaminophen covalent binding to examine the modifying effects of chronic ethanol with aging on the features responsible for drug conjugation and acetaminophen toxicity. Finally, the role of chronic ethanol in altering the hepatic energy state (ATP/(ADP + Pi) ratio) will be assessed by in vivo NMR. It is essential to explore such factors as aging and ethanol that will alter the conjugation pathways of drugs and the turnover processes of endogenous substrates. The program proposed herein is intended to address this important and currently neglected area of research.
