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
erne a;
Samo Andren
ek a;
Nata
a Kova
i
c;
Albin Kristl b;
Marija Bogataj b;
Uro
Urleb ab;
Ale
Mrhar b
erne a;
Samo Andren
ek a;
Nata
a Kova
i
c;
Albin Kristl b;
Marija Bogataj b;
Uro
Urleb ab;
Ale
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:
Drug Development and Industrial Pharmacy,
Volume
35,
Issue
11
November
2009
, pages 1293
- 1304
Subject:
Pharmaceutical Technology;
Formats available:
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(English)
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(English)
Also incorporating: Drug Design and Discovery
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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 |
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