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


CONCLUSIONS
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.
Smrdel
Polona
P
Lek Pharmaceuticals, Ljubljana, Slovenia.
Grabnar
Iztok
I
Locatelli
Igor
I
Cerne
Manica
M
Andrensek
Samo
S
Kovacic
Natasa
N
Kristl
Albin
A
Bogataj
Marija
M
Urleb
Uros
U
Mrhar
Ales
A
D000284:Administration, Oral; D000818:Animals; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D004151:Dipeptides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007155:Immunologic Factors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010797:Phthalimides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
D002214:Capsules; D003692:Delayed-Action Preparations; D004151:Dipeptides; D007155:Immunologic Factors; D010797:Phthalimides; C117773:N-(2-(2-phthalimidoethoxy)acetyl)-L-alanyl-D-glutamic acid