Aberrant Intestinal Absorption of Drugs

Aberrant Intestinal Absorption of Drugs

Aberrant intestinal absorption of drugs due to food interactions, drug interactions or genetic polymorphism has important clinical implications. Systemic exposure, thereafter the dynamics of pharmacologic and toxicological responses, may be affected dramatically by changes in intestinal transport of drugs. The long-term objective of my project is to understand the mechanism of intestinal absorption of bulky zwitterionic drugs, a large class of medicines to treat a variety of important diseases, such as allergy, bacteria and viral infections, neuralgia, etc. This information will provide the theoretical foundation in understanding drug-drug and food-drug interactions, predicting individual variability in drug absorption, designing drugs with better pharmacokinetic properties, and optimizing delivery systems for better oral absorption. Fexofenadine and cetirizine are selected as test compounds to prove the central hypothesis that a pair of apical (AP) and basolateral (BL) transporters creates vectorial transport system in the intestinal absorption of bulky zwitterionic drugs, and both transporters can determine the transcellular transport rate. The major goals of this research plan are: to identify intestinal transporters that mediate AP uptake of bulky zwitterionic drugs; to identify the key transporters and elucidate the mechanism of BL egress of bulky zwitterionic drugs; and to test if these mechanisms define the intestinal absorption of these compounds in intestinal segments. Several in vitro models including in transfected cell models, Caco-2 cells that retains intestinal transport mechanisms and intestinal tissues in Ussing chamber are utilized to identify AP uptake transporters and BL efflux transporters and determine their relative roles in intestinal drug absorption. In addition, suitable models with the right complement of transporters will be constructed to predict drug-drug and food-drug interactions of this class of drugs.