Mechanisms of region -dependent absorption of a weakly basic HIV protease inhibitor, indinavir: Clinical ramifications and comparison with nelfinavir.

Indinavir and nelfinavir are weakly basic HIV-protease inhibitors commonly used in antiretroviral therapy. They share similar physicochemical and pharmacological properties yet exhibit opposite food effects. Co-administration of high-caloric meals decreases the oral bioavailability of indinavir. The clinical consequences include a hindrance to patient compliance and the potential development of viral resistance. The objective of this research project is to compare the mechanisms of opposite food effects on indinavir and nelfinavir bioavailability, with a focus on the negative food effect on the pharmacokinetics of indinavir. The results demonstrate the application of region-dependent absorption studies to predict negative meal effects on oral drug availability. In vitro microsomes, in situ single-pass rat intestinal perfusion and Ussing chamber were among the experimental systems utilized in this project, coupled with HPLC and LC/MS bioanalytical methods. The rat was used as an animal model for investigation of intestinal transport and metabolism properties of indinavir and nelfinavir. It was determined that indinavir and nelfinavir exhibit fundamentally different intestinal absorption profiles. Specifically, nelfinavir is well absorbed throughout the small intestine while indinavir is only well absorbed in the upper small intestine. Further investigation into the intestinal transport processes responsible for this region-dependent absorption pattern of indinavir revealed that involvement of efflux transporter, p-glycoprotein, limited the absorption of indinavir in the lower small intestine while cytochrome P450IIIA, the major metabolizing enzyme of indinavir, served to promote apical uptake of indinavir. The negative food effect of indinavir is also associated with an elevation of gastric pH in HIV-infected patients after co-administration of a high-caloric protein meal. This particular meal effect may be the result of a decrease in the amount of indinavir available in solution in the GI tract compared to the fasted-state conditions. An in vitro crystallization study supported the hypothesis that precipitation may occur as the result of a change in pH. This study shows that an oral delivery strategy of high dose, poorly soluble, lipophilic drug candidates requires consideration of formulation and physicochemical properties, as well as biological properties such as the involvement and regional expression patterns of intracellular metabolizing enzymes and efflux transporters in the small intestine.PhDHealth and Environmental SciencesPharmaceutical sciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128011/2/3029374.pd