Plasma proteins can be dramatically decreased or increased in many disease states and physiological conditions. Current hypotheses suggest that such changes not only will affect the protein binding of many drugs but may also demonstrably modulated the elimination, distribution and pharmacologic response beyond that usually predicted by binding changes. Findings to date support the notion that plasma proteins play a more fundamental role in disposition and drug action than originally thought. However, only a few of the proteins invovled have been identified and the mechanisms invovled are poorly understood.
The specific aim of this project is to elucidate the mechanism(s) responsible for the """"""""protein effect"""""""" as a means of identifying the physiologic relevance of altered plasma protein concentrations. The proposed studies will aim to identify the mechanism(s) responsible for the """"""""protein effect"""""""" related to alpha-1-acid glycoprotein (AAG), an acute phase reactant, and to determine the importance of other acute phase reactants after induction of acute phase reactions. Investigations into the mechanisms of AAG will be studied in hepatocyte cultures aortic strip preparations, liver membane vesicles and in intact animals. The modulating effect of other acute phase reactants will be studied in hepatocyte cultures and in intact animals after induciton of the acute phase response by two different methods; surgery (laparotomy) and ischemia. The specific questions that we will explore are: 1) Is the effect of AAG on elimination a direct or indirect interation with enzymatic processes? 2) Which enzyme systems are invovled? 3) Does AAG alter the uptake/diffusion of drugs across cell membranes? 4) Will only drugs bound to AAG be affected? 5) Specifically, how does AAG affect the pharmacologic response of various alpha-1- adrenergic agonists and antagonists? 6) Is the pharmacologic response effect by AAG also modulated via changes in the concentration of active metabolites? 7) Why do different methods of inducing the acute phase response cause different changes in the metabolism that can not be explained by AAG changes alone? The results of the proposed studies will broaden our understanding of how plasma proteins such as the acute phase reactants alter the response and elimination of drugs. Knowledge of the underlying mechanistic nature of these phenomena will help in identifying those drugs which are affected by these compounds as well as identifying what the quantitative effect is. This information will imporove our ability to assess the impact of protein changes in disease states and on drug activity.
