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

• Published in: Drug development and industrial pharmacy 2009-11, Vol.35 (11), p.1293-1304
• Main Authors: Smrdel, Polona, Grabnar, Iztok, Locatelli, Igor, erne, Manica, Andrenšek, Samo, Kova i, Nataša, Kristl, Albin, Bogataj, Marija, Urleb, Uroš, Mrhar, Aleš
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Capsules; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Dipeptides - administration & dosage; Dipeptides - blood; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Dipeptides - toxicity; Dogs; Drug Evaluation, Preclinical - methods; Drug Stability; General pharmacology; Hydrogen-Ion Concentration; Immunologic Factors - administration & dosage; Immunologic Factors - blood; Immunologic Factors - chemistry; Immunologic Factors - pharmacokinetics; Immunologic Factors - toxicity; Immunomodulating activity; Injections, Intraperitoneal; Injections, Intravenous; Intestinal Absorption - drug effects; Intestines - metabolism; LK-423; Male; Mass Spectrometry; Medical sciences; Mice; Mice, Inbred Strains; Molecular Structure; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Phthalimides - administration & dosage; Phthalimides - blood; Phthalimides - chemistry; Phthalimides - pharmacokinetics; Phthalimides - toxicity; physicochemical properties; Rats; Rats, Wistar; Solubility; Toxicity Tests, Acute; Toxicity Tests, Chronic; toxicology
• ISSN: 0363-9045; 1520-5762
• DOI: 10.3109/03639040902889814

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.