Bile sequestrant resins are useful in the management of serum cholesterol levels, but their effectiveness is often compromised due to the large doses required which reduce compliance and give rise to side effects. The actual amount of bile salts sequestered in vivo is much less than the theoretical capacity of the resins. The reasons for this discrepancy have not been established and a better understanding of how factors common to the gastrointestinal tract affect bile salt binding may provide approaches for improving sequestrants. Results from studies investigating the effect of chloride ion, a predominant physiologic anion, on bile salt binding to cholestyramine in vitro are presented in this dissertation. Equilibrium binding results indicated that the effect of chloride ion alone does not account for the poor efficacy of sequestrants. The binding kinetics results indicated that the resins should rapidly equilibrate with bile salts in the intestine. In addition, bile salt binding has been shown to be reversible. By comparing the amount of chloride exchanged to the total amount of bile salts bound to cholestyramine it was possible to discriminate between the stoichiometric ion-exchange binding and additional non-specific adsorption. Results showed no significant differences between chloride exchange and total bile salt binding for several anions, indicating that binding is solely due to ion-exchange. Together, these experimental results suggested that sequestrants maintain binding equilibrium with bile salts and other anions during transit through the intestinal tract. Consequently, the reabsorption of bile salts in the ileum can influence the binding equilibria. As a means of gaining insight into the functioning of bile sequestrants in the GI tract and how reabsorption of bile salts affects the sequestering process, a multi-compartment mixing tank model based on human physiologic parameters was used to simulate the effect of bile sequestrants excretion of bile salts. Binding parameters were derived from the in vitro experiments. Incorporation of a reversible binding assumption into the model resulted in simulations closely matching human data. This finding supported the hypothesis that bile salt reabsorption compromises sequestrant activity. The model can also serve as a basis for screening potential sequestrants.Ph.D.PharmaceuticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/103916/1/9034475.pdfDescription of 9034475.pdf : Restricted to UM users only
