MECHANISMS OF CHOLESTEROL GALLSTONE DISSOLUTION

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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.