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INFLUENCE OF P-GLYCOPROTEIN, TRANSFER CLEARANCES, AND DRUG BINDING ON INTESTINAL METABOLISM IN CACO-2 CELL MONOLAYERS OR MEMBRANE PREPARATIONS: A THEORETICAL ANALYSIS

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Studies on the Caco-2 cell monolayer system that contained cytochrome P450 and P-glycoprotein activities had advanced the theory that increased intestinal metabolism resulted with increased drug efflux due to an increase in mean residence time (MRT) in the system. To confirm or refute the claim, we developed compartmental models to study the effects of intestinal secretion on the MRT and rates of metabolism under first-order and nonlinear conditions. The theoretical examinations showed that under first-order conditions, intestinal secretion increased the MRT of drug in all compartments but failed to increase the rate of metabolite formation or the total amount of metabolite formed. Instead, reduced metabolic rates arose with increased efflux from cell, either into the apical or the basolateral compartment. By contrast, under saturable metabolic conditions, there were some conditions found whereby rates of metabolism increased with intestinal secretion and rapid reabsorption, albeit the total amount of metabolite formed eventually equaled the administered dose. Intestinal secretion failed to induce higher rates of metabolism for other conditions (saturable cellular binding, cellular efflux, or cell entry). With saturation of metabolic enzymes, drug efflux brought about desaturation, and, upon rapid recovery of drug into the cellular compartment, higher rates of metabolite formation were attained. The simulation study showed that, under first-order conditions, intestinal secretion reduced the rate of metabolism even though the MRT was prolonged within the cell preparation. With nonlinear metabolism, however, instances may exist whereby higher rates of metabolism would result with secretion.

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