Kasiram Katneni's Project

Enhancement of drug permeability across intestinal epithelium by various formulation excipients.

Drugs are known to permeate across the intestinal epithelium by either passive diffusion or active transport. Transport of drugs by passive diffusion can be either by para-cellular or transcellular and is driven by drug concentration gradients across the absorptive cell (enterocyte). Active transport is medicated by various transporters that are present in the epithelial membrane and which can transport drugs against concentration gradient. Conversely, transport of drugs across the enterocyte can be limited by various transporters such as P-glycoprotein, MRP etc present in the intestinal epithelial membrane and which actively pump drugs from within the cell back into lumen - a process known as efflux. Absorption of drugs can be further limited by the activity of various drug metabolising enzymes, especially CYP3A, present in the enterocyte. For drugs with low permeability and for those that are substrates for efflux transporters and/or CYP3A, the presence of these biochemical barriers can lead to very poor and variable oral bioavailability. In order to improve the oral bioavailability of these classes of molecules it is necessary to understand the role of various efflux transporters and/or metabolic enzymes in drug permeability, and the potential utility of various formulation excipients to improve permeability and hence bioavailability. The current project is aimed at understanding the different mechanisms by which various excipients bring about improvement in the bio-availability of drugs.