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Protein Abundance of Clinically Relevant Multidrug Transporters along the Entire Length of the Human Intestine

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Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, Poland
Department of Clinical Pharmacology, University Medicine Greifswald, D-17487 Greifswald, Germany
§ Department of General and Transplantation Surgery, Pomeranian Medical University, Szczecin, Poland
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, United States
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, United States
*Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, Felix-Hausdorff-Str. 3, D-17487 Greifswald, Germany. Phone: +49-3834-865643. Fax: +49-3834-865631. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2014, 11, 10, 3547–3555
Publication Date (Web):August 26, 2014
https://doi.org/10.1021/mp500330y
Copyright © 2014 American Chemical Society

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    Abstract

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    Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied the mRNA expression (N = 33) and absolute protein content (N = 10) of clinically relevant transporters in healthy epithelium of the duodenum, the proximal and distal jejunum and ileum, and the ascending, transversal, descending, and sigmoidal colon of six organ donors (24–54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2 and 1.6 pmol/mg with the exception of those of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6–4.9 pmol/mg) that accounted for ∼50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1, and ASBT were significantly more abundant in jejunum and ileum than in colon. In contrast to this, the level of expression of ABCC2, ABCC3, and OCT3 was found to be highest in colon. Site-dependent differences in the levels of gene and protein expression were observed for ABCB1 and ASBT. Significant correlations between mRNA and protein levels have been found for ABCG2, ASBT, OCT3, and PEPT1 in the small intestine. Our data provide further physiological pieces of the puzzle required to predict intestinal drug absorption in humans.

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    Detailed mRNA expression data for the additionally measured transporters and nuclear receptors involved in the intestinal absorption of drugs, nutrients, and endogenous compounds as observed in intestines from six donors (Table 1) and correlations between intestinal mRNA expression of ABC transporters and nuclear receptors in intestinal tissues from six donors (Table 2). This material is available free of charge via the Internet at http://pubs.acs.org.

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