Our proposed research is aimed at providing a systematic approach and a mechanistic understanding of the kinetic factors associated with cholesterol gallstone dissolution in bile from the physical chemical standpoint. The question receiving special attention is that of the importance of cholesterol-lecithin (C-L) mesophase formation and dispersion during cholesterol monohydrate (ChM) dissolution. C-L mesophase formation/dispersion and micellar cholesterol solubilization are both believed to be important during ursodeoxycholic acid therapy and in the combination ursodeoxycholic acid/chenodeoxycholic acid therapy, and the relative importances of these two processes will be determined over a range of conditions of therapeutic significance in our cholesterol monohydrate (""""""""model gallstone"""""""") dissolution studies. Techniques and concepts newly developed in our laboratory will be utilized to determine the equilibria associated with cholesterol distributed in micelles and in the C-L mesophase and to determine the relationship between these equilibria and the kinetics of ChM dissolution. ChM pellet dissolution rates and simple micelle-mixed micelle coexistence data will be obtained and analyzed for wide ranges of bile salt and L concentrations. Simultaneous micellar ChM dissolution and C-L mesophase (vesicle) formation will be quantitatively studied in these bile salts-L systems. ChM dissolution rate patterns beyond the onset of the mesophase formation will be established form long term dissolution experiments. The silicone polymer method developed and validated recently in our laboratory will be employed to determine the cholesterol thermodynamic activity in the bile salt-L solutions unsaturated and supersaturated with respect to ChM. Cholesterol solubilization experiments will be conduced at various fixed bile salt activities (i.e., constant NMBS determined by the dialysis method developed in our laboratory) and various fixed lecithin concentrations in the system. These data will be used to construct, in effect, micellar solution - C-L mesophase phase diagrams at various cholesterol activities and bile salt activities, and the results will be employed in the analysis of the simultaneous micellar dissolution and C-L mesophase formation kinetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032472-07
Application #
3230907
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1982-11-01
Project End
1993-02-28
Budget Start
1991-03-01
Budget End
1993-02-28
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Liu, Chen-Lun; Higuchi, William I (2002) Cholesterol crystallite nucleation in supersaturated model biles from a thermodynamic standpoint. Biochim Biophys Acta 1588:15-25
Jain, U K; Higuchi, W I; Lee, P H et al. (1993) A rapid method for the measurement of cholesterol thermodynamic activity in bile salt-lecithin-cholesterol solutions. J Pharm Sci 82:714-20
Jain, U K; Higuchi, W I; Liu, C L et al. (1992) Cholesterol (thermodynamic) activity determinations in bile salt-lecithin-cholesterol systems and cholesterol-rich liquid crystalline mesophase formation. Pharm Res 9:792-9
Higuchi, W I; Lee, P H; Takayama, K et al. (1990) Cholesterol monomer activity and its role in understanding cholesterol saturation and crystallization. Hepatology 12:88S-91S;discussion 91S-93S
Higuchi, W I; Liu, C L; Adachi, Y et al. (1990) Equilibrium dialysis studies on aqueous taurocholate-lecithin solutions: further validation of the method. Hepatology 12:45S-49S;discussion 49S-50S