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In Silico Methods for Unraveling the Mechanistic Complexities of Intestinal Absorption: Metabolism-Efflux Transport Interactions

Graduate Group in Comparative Biochemistry, University of California, Berkeley, California (L.X.G.); The University of California San Francisco/University of California Berkeley Joint Graduate Group in Bioengineering, University of California, Berkeley and San Francisco, California (C.A.H.); and Department of Bioengineering and Therapeutic Sciences, BioSystems Group, University of California, San Francisco, California (C.A.H.)

We present a relatively simple, abstract, yet mechanistically realistic, in silico intestinal device (ISID). Its design enabled exploration of the mechanistic details of absorption for passively absorbed compounds that are also dual substrates of drug-metabolizing enzymes (CYP) and transporters (PGP), including P-glycoprotein. CYP and PGP, functioning as validated analogs of their referents, are autonomous software objects within the ISID. These and other autonomous objects were plugged together to form a device, an ISID, that represents intestinal features at different scales and levels of detail. Changes in proximal-to-distal levels of CYP and PGP are represented separately from the mechanisms that influence drug absorption and metabolism. Results for six proximal-to-distal CYP-PGP patterns are presented, along with results for different CYP/PGP ratios and amounts. We detected no CYP-PGP synergy. However, CYP-PGP antagonism was measured. Increasing the PGP/CYP ratio to 10 increased compound retention in the simulated lumen but did not increase total metabolism. Different proximal-to-distal CYP-PGP patterns, with and without simulated nonspecific, intracellular binding, had substantial effects on measures of absorption, metabolism, and metabolic extraction ratio within the ISID. The changes were due more to CYP than to PGP. The ISID represents a new class of models that is suitable for experimentation. It expands the repertoire of experimental methods for unraveling the mechanistic details of intestinal drug absorption and in anticipating the absorption consequences of drug interactions. To distinguish clearly in silico compounds and processes from corresponding intestinal structures and processes, we use small caps when referring to the former.