Interplay between P-glycoprotein-mediated efflux and cytochrome P4503A-mediated metabolism in the intestine Public Deposited

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  • March 21, 2019
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  • Knight, Beverly Michelle
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • Intestinal metabolism and drug efflux are recognized as two important barriers to drug absorption. The interactions between these factors may also be an important consideration in evaluating the drug-drug interaction potential of a given compound. Presented here are mechanistic studies that examine the interaction between the most germane metabolic enzyme/efflux transporter pair: cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp). In order to study this interaction, two model systems and two dual CYP3A/P-gp substrates were selected. The first model used was the CYP3A-expressing Caco-2 cell system. This system allowed for detailed mechanistic studies, with few confounding factors. The second system utilized was fresh mouse intestine (from P-gp competent and deficient mice) in a side-by-side diffusion chamber model. This model provided more physiologically relevant results with the caveat of increased complexity. The two drugs selected for study were terfenadine (an antihistamine) and loperamide (an antidiarrheal). In order to study the interplay between P-gp efflux and metabolism, the metabolism of each compound was measured during absorptive transport across Caco-2 cell monolayers and mouse tissue, in the presence or absence of P-gp activity. In the Caco-2 cell system, the results varied between the two compounds. Loperamide showed an increase in metabolism in the presence of the P-gp inhibitor GW918, while terfenadine showed no change. The lack of effect for terfenadine may be due to the action of a second transporter. In the mouse intestine, both compounds showed a higher metabolic rate in the absence of P-gp expression. For both systems, the effects were seen only within the low dose range, below about 50 [mu]M. This study also showed that terfenadine is metabolized about 60% by an enzyme that is inhibitable by quinidine (possibly CYP2D22) and only 40% by CYP3A in mouse intestine. The results presented in this dissertation indicate that P-gp efflux effectively decreases metabolism in intestine by decreasing intracellular concentrations. This conclusion is also supported by the pharmacokinetic modeling and simulations presented. The mechanistic information collected can provide insight into the nature of the CYP3A/P-gp interaction and can help in developing better models to predict in vivo intestinal drug-drug interactions.
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  • Thakker, Dhiren
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