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Permeability Dominates in Vivo Intestinal Absorption of P-gp Substrate with High Solubility and High Permeability

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Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, Department of Biomedical Informatics, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio 43210, and Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109
Cite this: Mol. Pharm. 2005, 2, 4, 329–340
Publication Date (Web):May 18, 2005
https://doi.org/10.1021/mp0499104
Copyright © 2005 American Chemical Society

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    Abstract

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    Three purposes are presented in this study:  (1) to study the in vivo regional dependent intestinal absorption of a P-gp substrate with high solubility and high permeability, (2) to study the gene expression difference in the various regions of the intestine, and (3) to study the contributions of P-gp or any other transporters for the absorption of a P-gp substrate. The in vivo permeability of verapamil and propranolol were determined by single-pass in situ intestinal perfusion in rat. The gene expression profiles were measured using Affymetrix GeneChip. Correlation analysis between drug in vivo permeability and expression of 3500 genes was performed with nonparametric bootstrap and ANOVA analysis. The permeability of verapamil and propranolol did not demonstrate regional dependency even though significant differences in gene expression were observed in various regions of the intestine. Verapamil permeability significantly correlates with propranolol permeability in both jejunum and ileum, but did not correlate with the permeability of other hydrophilic compounds (valacyclovir, acyclovir, and phenylalanine). Four different regions (duodenum, jejunum, ileum, and colon) showed distinct gene expression patterns with more than 70−499 genes showing at least 5-fold expression differences. Interestingly, P-gp expression is gradually increased by 6-fold from the duodenum to colon. Despite the distinct gene expression patterns in the various regions of the intestine, verapamil permeability did not correlate with any gene expression from 3500 expressed genes in the intestine. A 2−6-fold P-gp expression difference did not seem to associate verapamil permeability in the various intestinal regions in vivo. These data suggest that P-gp plays a minimal role in the in vivo intestinal absorption process of verapamil with high water solubility and high membrane permeability. The intestinal absorption of verapamil in vivo is primarily dominated by its high permeability. However, it is important to note that the findings in this paper do not undermine the importance of P-gp in oral drug bioavailability, drug disposition from the liver, drug efflux from the blood−brain barrier, and drug−drug interaction.

    Keywords: Permeability; P-gp; intestine; gene expression; verapamil; correlation; microarray

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     College of Pharmacy, The Ohio State University.

     Food and Drug Administration.

    §

     College of Medicine and Public Health, The Ohio State University.

     University of Michigan.

    *

     To whom correspondence should be addressed. G.L.A.:  Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109; tel, 734-764-2440; fax, 734-763-6423; e-mail, [email protected]. D.S.:  Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 232 Parks Hall, 500 W. 12th Ave., Columbus, OH 43210; tel, 614-292-4381; fax, 614-292-7766; e-mail, [email protected].

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