title: Concentration dependence of 5-aminosalicylic acid pharmacological actions in intestinal mucosa after oral administration of a pH-dependent formulation.
abstract: Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH ≥ 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients.
authors.affiliation: Central Research Laboratories, ZERIA Pharmaceutical Co., Ltd., Saitama, Japan. masamichi-hirayama@zeria.co.jp
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirayama
authors.forename: Ryoko
authors.initials: R
authors.lastname: Toda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ozaki
authors.forename: Junko
authors.initials: J
authors.lastname: Hasegawa
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Naraki
authors.forename: Yukari
authors.initials: Y
authors.lastname: Haraguchi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hori
authors.forename: Takao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Mineo
authors.initials: M
authors.lastname: Takei
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Mera
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yoshii
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawabata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D004285:Dogs; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D019804:Mesalamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D007975:Leukotriene B4; D019804:Mesalamine