ebooks logo journals logo reference works logo abstract databases logo
bullet  SIGN IN Register | Why Register? | Got a Voucher? alerts   marked lists   shopping cart 
Advert: Informa Healthcare - http://www.informahealthcare.com

informaworld

HOME   |   SEARCH   |   BROWSE
    Issues List       Latest Issue       Forthcoming Articles       Volume 35 Issue 11       Subscribe       Article       References       Related articles      
<< firstfirst   < prevprev   Table of contentstoc   next >next   last >>last
Publisher Logo Publication Cover
Search within this journal
iOpen

Physicochemical and preclinical pharmacokinetic and toxicological evaluation of LK-423—a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity 

Authors: Polona Smrdel ab;  Iztok Grabnar b;  Igor Locatelli b;  Manica Ccaronerne a;  Samo Andrenscaronek a;  Natascarona Kovaccaroniccaron c;  Albin Kristl b;  Marija Bogataj b;  Uroscaron Urleb ab; Alescaron Mrhar b
Affiliations:   a Lek Pharmaceuticals, Ljubljana, Slovenia
b Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
c Erico Velenje, Institute of Ecological Research, Velenje, Slovenia
DOI: 10.3109/03639040902889814
Publication Frequency: 12 issues per year
Published in: journal Drug Development and Industrial Pharmacy, Volume 35, Issue 11 November 2009 , pages 1293 - 1304
Formats available: HTML (English) : PDF (English)
Also incorporating: Drug Design and Discovery
Article Requests: Order Reprints : Request Permissions


Abstract

Introduction: LK-423 is a new phthalimido-desmuramyl-dipeptide derivative with immunomodulating activity. As optimized delivery to the site of action appears crucial for further preclinical development of LK-423, the aim of this study was to perform a physicochemical and preclinical pharmacokinetic and toxicological evaluation. Methods: The solubility, partition coefficient, permeability, and stability profile were determined. Pharmacokinetics were evaluated in rats following intravenous and oral application of LK-423, and in dogs after intravenous administration and oral administration of microcapsules, designed for colon-specific delivery of LK-423 based on pH-, time-, and enzyme-controlled release mechanisms. Additionally, the acute and subchronic toxicity was examined. Results and discussion: LK-423 is hydrophilic, sparingly to slightly soluble, and poorly permeable. Stability profile in aqueous solution is pH dependent. A pharmacokinetic study following intravenous application to rats and dogs revealed that LK-423 is rapidly eliminated with a short terminal phase half-life, and high plasma clearance, as well as a limited distribution to the peripheral tissue. Oral bioavailability of LK-423 is low, presumably due to low permeability. Debris of insoluble microcapsule coating in feces and obtained plasma concentration profiles confirm that LK-423 microcapsules are a promising approach for local treatment of inflammatory diseases of the large intestine. Acute and a subchronic toxicity results indicate that LK-423 is a safe and nontoxic drug under the applied experimental conditions.
Keywords: Immunomodulating activity; LK-423; pharmacokinetics; physicochemical properties; toxicology
view references (25)
Bookmark with:
  • CiteULike
  • Del.icio.us
  • BibSonomy
  • Connotea
  • More bookmarks
Privacy Policy | Terms & Conditions | Accessibility | RSS
FAQs in: English . Français . Español . 中文(简体和繁體)
© 2010 Informa plc