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Gut metabolism
Many attempts at IVIVE fail to address the impact of drug metabolism by enzymes in the gut wall, as part of the ‘first-pass effect’ in concert with hepatic metabolism.
In the Simcyp Simulator, this is accommodated by a model that takes account of both enterocytic permeability and enterocytic blood flow as determinants of gut metabolism (Yang et al., 2007). The model incorporates net metabolism by gut CYP and UGT enzymes using in vitro data on intrinsic clearance per unit enzyme, the abundance of enzyme in various sections of the gut and a hybrid term (Qgut) representing transit through the enterocyte. Qgut is determined experimentally from in vitro systems, such as Caco-2, MDCK or LLC-PK1 cells, and incorporates the interplay between efflux transport (mediated by P-gp, MRP2 and/or BCRP), with CYP and UGT enzymes.
