| Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. | |
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MedLine Citation:
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PMID: 19541926 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Sulfasalazine is characterized by low intestinal absorption, which essentially enables its colonic targeting and therapeutic action. The mechanisms behind this low absorption have not yet been elucidated. The purpose of this study was to investigate the role of efflux transporters in the intestinal absorption of sulfasalazine as a potential mechanism for its low small-intestinal absorption and colonic targeting following oral administration. The effects of P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on sulfasalazine bidirectional permeability were studied across Caco-2 cell monolayers, including dose-response analysis. Sulfasalazine in vivo permeability was then investigated in the rat jejunum by single-pass perfusion, in the presence vs. absence of inhibitors. Sulfasalazine exhibited 19-fold higher basolateral-to-apical (BL-AP) than apical-to-basolateral (AP-BL) Caco-2 permeability, indicative of net mucosal secretion. MRP2 inhibitors (MK-571 and indomethacin) and BCRP inhibitors [fumitremorgin C (FTC) and pantoprazole] significantly increased AP-BL and decreased BL-AP sulfasalazine Caco-2 transport in a concentration-dependent manner. No effect was observed with the P-gp inhibitors verapamil and quinidine. The IC50 values of the specific MRP2 and BCRP inhibitors MK-571 and FTC on sulfasalazine secretion were 21.5 and 2.0 microM, respectively. Simultaneous inhibition of MRP2 and BCRP completely abolished sulfasalazine Caco-2 efflux. Without inhibitors, sulfasalazine displayed low (vs. metoprolol) in vivo intestinal permeability in the rat model. MK-571 or FTC significantly increased sulfasalazine permeability, bringing it to the low-high permeability boundary. With both MK-571 and FTC present, sulfasalazine displayed high permeability. In conclusion, efflux transport mediated by MRP2 and BCRP, but not P-gp, shifts sulfasalazine permeability from high to low, thereby enabling its colonic targeting and therapeutic action. To our knowledge, this is the first demonstration of intestinal efflux acting in favor of oral drug delivery. |
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Authors:
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Arik Dahan; Gordon L Amidon |
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Publication Detail:
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Type: Journal Article Date: 2009-06-18 |
Journal Detail:
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Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 297 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2009-07-22 Completed Date: 2009-08-25 Revised Date: 2013-06-04 |
Medline Journal Info:
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Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
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Languages: eng Pagination: G371-7 Citation Subset: IM |
Affiliation:
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The University of Michigan College of Pharmacy, Department of Pharmaceutical Sciences, Ann Arbor, Michigan 48109-1065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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2-Pyridinylmethylsulfinylbenzimidazoles
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pharmacology ATP-Binding Cassette Transporters / antagonists & inhibitors, metabolism* Administration, Oral Animals Biological Transport Caco-2 Cells Colon / drug effects, metabolism* Dose-Response Relationship, Drug Drug Delivery Systems Humans Indoles / pharmacology Indomethacin / pharmacology Intestinal Absorption* Intestine, Small / drug effects, metabolism* Kinetics Male Multidrug Resistance-Associated Proteins / antagonists & inhibitors, metabolism* Neoplasm Proteins / antagonists & inhibitors, metabolism* P-Glycoprotein / metabolism Perfusion Permeability Propionates / pharmacology Quinolines / pharmacology Rats Rats, Wistar Sulfasalazine / administration & dosage, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/2-Pyridinylmethylsulfinylbenzimidazoles; 0/ABCG2 protein, human; 0/Abcc2 protein, rat; 0/Abcg2 protein, rat; 0/Indoles; 0/Multidrug Resistance-Associated Proteins; 0/Neoplasm Proteins; 0/P-Glycoprotein; 0/Propionates; 0/Quinolines; 0/multidrug resistance-associated protein 2; 115104-28-4/verlukast; 53-86-1/Indomethacin; 55387-45-6/tryptoquivaline; 599-79-1/Sulfasalazine; D8TST4O562/pantoprazole |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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