| Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters. | |
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MedLine Citation:
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PMID: 12973823 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Psoriasis is a chronic inflammatory skin disease. Its treatment is based on the inhibition of proliferation of epidermal cells and interference in the inflammatory process. A new systemic antipsoriasis drug, which consists of dimethylfumarate and ethylhydrogenfumarate in the form of their calcium, magnesium and zinc salts has been introduced in Europe with successful results. In the present study, a homologous series of mono- and diesters of fumaric acid has been studied with respect to the sites and kinetics of presystemic ester degradation using pancreas extract, intestinal perfusate, intestinal homogenate and liver S9 fraction. In addition, intestinal permeability has been determined using isolated intestinal mucosa as well as Caco-2 cell monolayers, in order to obtain estimates of the fraction of the dose absorbed for these compounds. Relationships between the physicochemical properties of the fumaric acid esters and their biological responses were investigated. The uncharged diester dimethylfumarate displayed a high presystemic metabolic lability in all metabolism models. It also showed the highest permeability in the Caco-2 cell model. However, in permeation experiments with intestinal mucosa in Ussing-type chambers, no undegraded DMF was found on the receiver side, indicating complete metabolism in the intestinal tissue. The intestinal permeability of the monoesters methyl hydrogen fumarate, ethyl hydrogen fumarate, n-propylhydrogen fumarate and n-pentyl hydrogen fumarate increased with an increase in their lipophilicity, however, their presystemic metabolism rates likewise increased with increasing ester chain length. It is concluded that for fumarates, an increase in intestinal permeability of the more lipophilic derivatives is counterbalanced by an increase in first-pass extraction. |
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Authors:
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D Werdenberg; R Joshi; S Wolffram; H P Merkle; P Langguth |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biopharmaceutics & drug disposition Volume: 24 ISSN: 0142-2782 ISO Abbreviation: Biopharm Drug Dispos Publication Date: 2003 Sep |
Date Detail:
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Created Date: 2003-09-15 Completed Date: 2004-05-24 Revised Date: 2013-04-01 |
Medline Journal Info:
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Nlm Unique ID: 7911226 Medline TA: Biopharm Drug Dispos Country: England |
Other Details:
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Languages: eng Pagination: 259-73 Citation Subset: IM |
Copyright Information:
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Copyright 2003 John Wiley & Sons, Ltd. |
Affiliation:
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Department of Applied BioSciences, Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atenolol / pharmacology Biological Availability Caco-2 Cells Cell Membrane Permeability / drug effects, physiology Cells, Cultured Enzyme Inhibitors / pharmacology Fumarates / chemistry, metabolism, pharmacokinetics*, therapeutic use* Humans Intestinal Absorption / drug effects*, physiology Intestinal Mucosa / drug effects, metabolism Intestines / enzymology Liver Extracts / metabolism Microvilli / drug effects, metabolism Pancreatic Extracts / metabolism Propranolol / pharmacology Psoriasis / drug therapy* Swine |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Fumarates; 0/Liver Extracts; 0/Pancreatic Extracts; 2459-05-4/ethyl fumarate; 29122-68-7/Atenolol; 525-66-6/Propranolol; FO2303MNI2/dimethyl fumarate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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