title: Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters.
abstract: 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.
authors.affiliation: Department of Applied BioSciences, Swiss Federal Institute of Technology Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Werdenberg
authors.forename: R
authors.initials: R
authors.lastname: Joshi
authors.forename: S
authors.initials: S
authors.lastname: Wolffram
authors.forename: H P
authors.initials: HP
authors.lastname: Merkle
authors.forename: P
authors.initials: P
authors.lastname: Langguth
mesh_terms: D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005650:Fumarates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D008110:Liver Extracts / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D010184:Pancreatic Extracts / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy*; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D005650:Fumarates; D008110:Liver Extracts; D010184:Pancreatic Extracts; D001262:Atenolol; D011433:Propranolol; D000069462:Dimethyl Fumarate; C061175:ethyl fumarate