It has become apparent that a change in the protein concentration will modulate the elimination of drugs not only through changes in the unbound fraction of drug in serum but also through an additional """"""""protein effect"""""""". This """"""""protein effect"""""""" varies among drugs. The mechanisms involved have not been established, although several theories have been put forward. If changes in the protein concentration can also affect the unbound concentration -- response relationship is, on the other hand, not established.
The specific aim of this project is to elucidate the mechanism(s), responsible for the """"""""protein effect"""""""" and to determine its significance. The studies will focus on determining the effect of the two main drug binding proteins in serum, albumin and alpha-1-acid glycoprotein. The mechanisms responsible for modulating the metabolism of drugs will be determined using the isolated rat liver perfusion preparation. The unbound concentration-response relationship measurements will be carried out in the isolated perfused guinea pig heart. Test drugs to be studied will be primarily antiarrhythmic and antihypertensive agents. Answers to the following questions will be sought: 1) Do protein concentration changes alter the unbound concentration-response relationship? 2) Do the plasma proteins interact with specific protein receptors? 3) Is the interaction non-specific? 4) Will interaction of albumin with alpha-1-acid glycoprotein enhance or decrease the """"""""protein effect""""""""? 5) Is the effect direct or indirect? 6) Is the effect occurring at the cellular level or is it related to the hepatic architecture? 7) Is the effect qualitatively and quantitatively different for high and low extraction ratio compounds? The results of the proposed studied will provide new insight into our understanding of serum proteins as they relate to the response and elimination of cardiovascular drugs, and will assist in optimizing drug delivery to the cardiac patient by improving our ability to assess the impact of protein changes in disease state on this class of drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM035192-02
Application #
3287517
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
Fiscal Year
1986
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