Targeting of drugs to the gastrointestinal epithelia via oral liposomes.

The purpose of this research was to explore the potential for targeted drug delivery to inflamed intestine for the treatment of inflammatory bowel disease (IBD). Current therapeutic regimens for IBD could be improved by increasing intestinal drug concentrations and decreasing systemic side effects. The uptake and elimination of 5ASA (a common drug for IBD) in intestinal epithelial cells and systemic circulation was studied. 5ASA is rapidly absorbed from the proximal intestine by passive diffusion. A pH-independent partition coefficient (P$\sb{\rm octanol/water}$ = 0.03) suggests poor lipid membrane partitioning of 5ASA. However, a low capacity active intracellular uptake was demonstrated in Caco-2 cells consistent with 5ASA's epithelial antiinflammatory action. A significant intestinal metabolism of 5ASA in rat single-pass perfusions was confirmed with a unidirectional elimination of N-acetyl 5ASA across the apical membrane by high capacity efflux carriers. The unidirectional elimination of N-acetyl 5ASA generated by the intestinal epithelial cells into the intestinal lumen provides fecal metabolite as an indicator of intestinal 5ASA elimination which constitutes over 50% of the total drug elimination for sustained-release formulations. While 5ASA is taken up into intestinal epithelial cells by low capacity carriers, it primarily enters the systemic circulation by passive diffusion via paracellular pathways. Formulations to increase drug levels in the intestinal epithelia would result in a greater than proportional systemic drug exposure. As demonstrated in simulation, sustained release drug delivery bypasses rapid proximal systemic absorption but provides low drug levels in the epithelia by limiting drug release in the lumen. Pharmacokinetic studies showed 5ASA encapsulated in liposomes significantly decrease systemic 5ASA absorption as compared to 5ASA solutions at the same concentration. Tissue drug measurements demonstrated that liposome encapsulation increased drug levels in the intestine by 2 fold over drug solution. Further study in an ulcerative colitis rat model yielded an additional 2-fold 5ASA accumulation with liposome formulation in the inflamed intestine as compared to normal intestine with no significant increase in the systemic drug absorption. Confocal studies on rat tissue and Caco-2 cells showed that a great number of liposomes nonspecifically bind to the epithelial surface and penetrate into the epithelia facilitating high local drug levels and sustained release.PhDHealth and Environmental SciencesPathologyPharmaceutical sciencesPharmacologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/131585/2/9910035.pd