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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM035192-04
Application #
3287514
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-09-01
Project End
1992-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Qin, M; Oie, S (1994) Does alpha 1-acid glycoprotein act as a non-functional receptor for alpha 1-adrenergic antagonists? J Pharm Pharmacol 46:896-901
Oie, S; Jacobson, M A; Abrams, D I (1993) Alpha 1-acid glycoprotein levels in AIDS patients before and after short-term treatment with zidovudine (ZDV) J Acquir Immune Defic Syndr 6:531-3
Parivar, K; Tolentino, L; Taylor, G et al. (1992) Elimination of non-reactive and weakly reactive human alpha 1-acid glycoprotein after induction of the acute phase response in rats. J Pharm Pharmacol 44:447-50
Chiang, J; Hermodsson, G; Oie, S (1991) The effect of alpha 1-acid glycoprotein on the pharmacological activity of alpha 1-adrenergic antagonists in rabbit aortic strips. J Pharm Pharmacol 43:540-7
Chiang, J; Oie, S (1990) Pharmacologic activity of prazosin is decreased by alpha-1-acid glycoprotein in vivo. J Pharmacol Exp Ther 254:324-9
Oie, S; Chiang, J (1989) Alteration in the pharmacologic activity of alpha 1 adrenergic antagonists by alpha-1-acid glycoprotein. Prog Clin Biol Res 300:235-8
Oie, S; Yang, Y H (1988) Effect of altered albumin concentrations on elimination of unbound prazosin in vivo in the rat and in the isolated perfused rat liver. J Pharm Sci 77:948-51
Braun, J; Sorgel, F; Gluth, W P et al. (1988) Does alpha 1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment? Eur J Clin Pharmacol 35:313-7
Oie, S; Fiori, F; Chiang, J (1987) Decreased elimination of unbound prazosin in the presence of alpha 1-acid glycoprotein in the rat in vivo. J Pharmacol Exp Ther 241:934-8