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Biopharm Drug Dispos. 2010 May;31(4):215-27. doi: 10.1002/bdd.704.

Interplay of transporters and enzymes in the Caco-2 cell monolayer: I. effect of altered apical secretion.

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Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.


Interactions are expected between transporters and enzymes that compete for the substrate within the cell, and controversy exists for data interpretation on the interplay between transporters and enzymes. In the Caco-2 cell monolayer, the increase in mean residence time (MRT) of drug accompanying increased secretion has been construed as the reason for increased metabolism, whereas others hold an opposite view that increased secretion would evoke decreased metabolism in this closed system. A catenary Caco-2 cell model was used to simulate the effects of altered secretion on metabolism, estimated as the fraction of dose metabolized (f(met)) or the extraction ratio (ER). The simulations showed that both f(met) and ER varied inversely with the transporter-mediated intrinsic clearance for apical secretion (CL(int,sec)) under linear conditions. Under non-linear conditions of saturable metabolism, apical absorption, basolateral influx or efflux, the simulated f(met) consistently bore a reciprocal relationship with CL(int,sec). For saturable apical absorption or basolateral efflux, a reciprocal relationship between the ER and CL(int,sec) was also found. However, under conditions of saturable metabolism or basolateral influx, the pattern of change in the ER became dependent on the administration sites, showing increasing patterns for apical dosing but decreasing patterns for basolateral dosing with increasing values of CL(int,sec). In general, f(met) consistently demonstrated an inverse relationship with CL(int,sec), whereas ER, failing to include the drug in the donor side, would not show the same pattern of change in metabolism especially for apical dosing, since a substantial amount of drug was back-secreted into the apical compartment.

[Indexed for MEDLINE]

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