Received for publication December 18, 2007.
Revised April 22, 2008.
Accepted for publication April 23, 2008.

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

Abstract

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 analogues 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 ten increased compound retention in the simulated lumen, but did not increase total metabolism. Different proximal-to-distal CYP-PGP patterns, with and without simulated non-specific, 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.

Key words: absorption, cellular transport, CYP3A, drug absorption, drug efflux, intestinal transport, kinetic modeling, membrane transport, Monte Carlo simulations, p-glycoprotein