Influence of P-glycoprotein, transfer clearances, and drug binding on intestinal metabolism in Caco-2 cell monolayers or membrane preparations: a theoretical analysis

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Debbie TamK Sandy Pang

Abstract

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 met...Continue Reading

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Citations

Sep 5, 2006·Pharmaceutical Research·Timo KorjamoPaavo Honkakoski
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Oct 13, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Huadong Sun, K Sandy Pang
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Related Concepts

Pharmaceutical Preparations
Intestines
Total Body Clearance Rate
Caco-2 Cells
P-Glycoprotein

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