Investigation the effect of malnutrition on the absorption and permeability of drugs

Pathophysiological changes seen in malnutrition affect drug absorption from the gastrointestinal tract. The aim of thesis is to investigate the absorption/permeability of model compounds (metoprolol and atenolol) absorbed from the intestines by different mechanisms (transcellular and paracellular) in malnourished rats using in vitro cell culture and in situ intestinal perfusion studies and their evaluation by in vivo and pharmacokinetic modeling studies. In addition, the change in absorption and permeability of metoprolol were investigated using P-gp, CYP3A4, and PMAT inhibitors (elacridar, ketoconazole, and verapamil). The amount of compounds in samples obtained from the experiments was analyzed by validated HPLC methods. In vivo data were evaluated by model-independent method, minimal physiologically based pharmacokinetic modeling and population pharmacokinetic analyses and pharmacokinetic parameters were estimated. According to the results of transport studies, while the permeability of atenolol increased in malnourished HCT-8 and Caco-2 cells (p < 0.05), no significant difference was observed in the permeability of metoprolol in malnourished cells. Results from in situ intestinal perfusion studies showed that permeability of atenolol across jejunum and ileum increased in malnourished groups (p < 0.05), while its colonic permeability did not change. On the other hand, while the permeability of metoprolol across jejunum and ileum did not change in malnutrition, its colonic permeability decreased significantly (p < 0.05). In vivo plasma concentration-time profiles were characterized by 2-3 stage zero-order absorption kinetics, and increase in drug exposure in malnourished rats was explained. The results obtained from this study proved that the permeability/absorption of model compounds may change in malnutrition.